Amide derivatives and medicinal use thereof

ABSTRACT

The present invention relates to an amide derivative of the formula (1), having a C5a receptor antagonistic action 
                         
wherein each symbol is as defined in the specification.
 
     The above-mentioned amide derivative, an optically active form thereof and a pharmaceutically acceptable salt thereof are promising as an agent for the treatment or prophylaxis of diseases or syndromes caused by inflammation caused by C5a [e.g., autoimmune diseases such as rheumatism, systemic lupus erythematosus and the like, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like, atherosclerosis, cardiac infarction, brain infarction, psoriasis, Alzheimer&#39;s disease and serious organ injury (e.g., pneumonia, nephritis, hepatitis and pancreatitis and the like) due to activation of leukocytes caused by ischemia reperfusion, trauma, burn, surgical invasion and the like]. Moreover, they are useful as a therapeutic or prophylactic agent for the infectious diseases caused by bacteria and virus that invade via a C5a receptor.

This application is a U.S. national stage of International ApplicationNo. PCT/JP01/07977 filed Sep. 14, 2001.

TECHNICAL FIELD

The present invention relates to an amide derivative showing a C5areceptor antagonistic action and useful for the prophylaxis or treatmentof autoimmune diseases such as rheumatism, systemic lupus erythematosusand the like, sepsis, adult respiratory distress syndrome, chronicobstructive pulmonary disease, allergic diseases such as asthma and thelike, atherosclerosis, cardiac infarction, brain infarction, psoriasis,Alzheimer's disease or serious organ injury (e.g., pneumonia, nephritis,hepatitis and pancreatitis and the like) due to activation of leukocytescaused by ischemia reperfusion, trauma, burn, surgical invasion and thelike, an optically active form thereof a pharmaceutically acceptablesalt thereof and pharmaceutical use thereof.

BACKGROUND ART

When the complement system is activated, the protein of the complementsystem is enzymolysed and fragments having various physiologicalactivities are produced. One of the fragments, complement component C5a,is a glycoprotein having a molecular weight of about 11,000, consists of74 amino acids and has a strong inflammation inducing action. C5a has abroad range of actions such as smooth muscle contraction, promotion ofblood vessel permeability, migration of leukocyte, degranulation ofleukocyte, production of reactive oxygen species, reinforcement ofantibody production, induction of production of cytokine, TNF (tumornecrosis factor) and leukotriene, and the like, and is said to be acausative substance of diseases such as autoimmune diseases (e.g.,rheumatism and systemic lupus erythematosus and the like), sepsis, adultrespiratory distress syndrome, chronic obstructive pulmonary disease,allergic diseases (e.g., asthma and the like), atherosclerosis, cardiacinfarction, brain infarction, psoriasis, Alzheimer's disease, seriousorgan injuries (e.g., pneumonia, nephritis, hepatitis, pancreatitis andthe like) due to activation of leukocytes caused by ischemiareperfusion, trauma, burn, surgical invasion and the like, and the like[Annu. Rev. Immunol., vol. 12, pp. 775-808 (1994), Immunopharmacology,vol. 38, pp. 3-15 (1997), Curr. Pharm. Des., vol. 5, pp. 737-755 (1999)and IDrugs, vol. 2, pp. 686-693 (1999)].

Accordingly, a non-peptide small molecular compound having a C5areceptor antagonistic action is expected as a novel non-steroid typeantiinflammatory drug. In addition, it can be expected as a prophylacticor therapeutic drug of infectious diseases caused by bacteria or virusthat invades via a C5a receptor.

As regards the C5a antagonist, for example, the following patentapplications have been published. JP-A-10-182648 discloses TAN-2474related compounds having a C5a antagonistic action. In addition, thespecification of WO94/07815 discloses peptide derivatives having a C5areceptor antagonistic action, the specification of WO99/00406 disclosescyclic peptide derivatives having a C5a receptor antagonistic action.

Heretofore, however, a pharmaceutical drug, that prevents or treatsdiseases or syndromes due to the inflammation caused by C5a byinhibiting the action of C5a, has not been developed.

DISCLOSURE OF THE INVENTION

In view of the above-mentioned situation, the present inventors haveconducted intensive studies with the aim of finding a non-peptidecompound having a C5a receptor antagonistic action. As a result, theyhave found that an amide derivative according to the present inventionshows a C5a receptor antagonistic action, which resulted in thecompletion of the present invention.

Accordingly, the present invention provides the following.

1. An amide derivative represented by the formula (1)

wherein

-   R¹, R² and R³    -   are the same or different and each is hydrogen atom, alkyl group        optionally having substituents, alkenyl group optionally having        substituents, alkynyl group optionally having substituents,        cycloalkyl group optionally having substituents, aryl group        optionally having substituents, heteroaryl group optionally        having substituents, arylalkyl group optionally having        substituents, heteroarylalkyl group optionally having        substituents, alkoxy group optionally having substituents,        aryloxy group, arylalkyloxy group, acyloxy group optionally        having substituents, halogen atom, hydroxyl group, nitro group,        cyano group, acyl group, mercapto group, alkylthio group,        alkylsulfonyl group, amino group, alkylamino group, dialkylamino        group, cyclic amino group, carbamoyl group optionally having        substituents, alkoxycarbonyl group, carboxyl group, acylamino        group, sulfamoyl group optionally having substituents or        haloalkyl group, or any two of R¹, R² and R³ in combination with        the adjacent carbon atom may form a ring,-   a, b, c, d and e    -   are each carbon atom, or 1 or 2 of a, b, c, d and e is(are)        nitrogen atom(s) (provided that the nitrogen atom here may be        bonded to oxygen atom to form amine oxide) and the rest are        carbon atoms,-   R⁴, R⁵ and R⁶    -   are the same or different and each is hydrogen atom, alkyl group        optionally having substituents, alkenyl group optionally having        substituents, alkynyl group optionally having substituents,        cycloalkyl group optionally having substituents, aryl group        optionally having substituents, heteroaryl group optionally        having substituents, arylalkyl group optionally having        substituents, heteroarylalkyl group optionally having        substituents, alkoxy group optionally having substituents,        aryloxy group, arylalkyloxy group, acyloxy group optionally        having substituents, halogen atom, hydroxyl group, nitro group,        cyano group, acyl group, mercapto group, alkylthio group,        alkylsulfonyl group, amino group, alkylamino group, dialkylamino        group, cyclic amino group, carbamoyl group optionally having        substituents, alkoxycarbonyl group, carboxyl group, acylamino        group, sulfamoyl group optionally having substituents, haloalkyl        group or haloalkyloxy group,-   A is hydrogen atom, cycloalkyl group optionally having substituents,    aryl group optionally having substituents, heteroaryl group    optionally having substituents or cyclic amino group optionally    having substituents,-   W¹ and W²    -   are the same or different and each is a bond or alkylene(C_(n))        optionally having substituents wherein n is an integer of 1 to        3,-   X is oxygen atom or sulfur atom,-   Y is a bond, oxygen atom, —CO—, —N(R⁷)— wherein R⁷ is hydrogen atom    or alkyl group optionally having substituents, —SO_(m)— wherein m is    an integer of 0 to 2, —CON(R⁸)— wherein R⁸ is hydrogen atom or alkyl    group optionally having substituents or —N(R⁹)CO— wherein R⁹ is    hydrogen atom or alkyl group optionally having substituents), and-   Z is a bond or alkylene group optionally having substituents    (hereinafter sometimes abbreviated as amide derivative (1)),    an optically active form thereof or pharmaceutically acceptable salt    thereof.    2. The amide derivative of the above-mentioned 1, wherein, in the    formula (1),    R¹, R² and R³ are the same or different and each is hydrogen atom,    alkyl group optionally having substituents, alkenyl group optionally    having substituents, alkynyl group optionally having substituents,    cycloalkyl group, alkoxy group optionally having substituents,    acyloxy group optionally having substituents, halogen atom, hydroxyl    group, nitro group, cyano group, acyl group, mercapto group,    alkylthio group, alkylsulfonyl group, amino group, alkylamino group,    dialkylamino group, cyclic amino group, carbamoyl group,    alkoxycarbonyl group, carboxyl group, tetrazolyl group, oxadiazolyl    group, sulfamoyl group or haloalkyl group,    a, b, c, d and e are each carbon atom, or 1 or 2 of a, b, c, d and e    is(are) nitrogen atom(s) and the rest are carbon atoms,    R⁴, R⁵ and R⁶ are the same or different and each is hydrogen atom,    alkyl group optionally having substituents, alkenyl group optionally    having substituents, alkynyl group optionally having substituents,    cycloalkyl group, alkoxy group optionally having substituents,    acyloxy group optionally having substituents, halogen atom, hydroxyl    group, nitro group, cyano group, acyl group, mercapto group,    alkylthio group, alkylsulfonyl group, amino group, alkylamino group,    dialkylamino group, cyclic amino group, carbamoyl group,    alkoxycarbonyl group, carboxyl group, tetrazolyl group, oxadiazolyl    group, sulfamoyl group or haloalkyl group,    A is hydrogen atom, cycloalkyl group, aryl group optionally having    substituents, heteroaryl group optionally having substituents or    cyclic amino group,    W¹ and W² are the same or different and each is a bond or alkylene    (C_(n)) optionally having substituents wherein n is an integer of 1    to 3,    X is oxygen atom or sulfur atom,    Y is a bond, oxygen atom, —CO—, —N(R⁷)— wherein R⁷ is hydrogen atom    or alkyl group optionally having substituents, —SO_(m)— wherein m is    an integer of 0 to 2, —CON(R⁸)— wherein R⁸ is hydrogen atom or alkyl    group optionally having substituents or —N(R⁹)CO— wherein R⁹ is    hydrogen atom or alkyl group optionally having substituents, and    Z is a bond or alkylene group optionally having substituents,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    3. The amide derivative of the above-mentioned 2, wherein a, b, c, d    and e in the formula (1) are all carbon atoms,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    4. The amide derivative of the above-mentioned 1, wherein R¹, R² and    R³ in the formula (1) are the same or different and each is hydrogen    atom, alkyl group having 2 to 4 carbon atoms or alkoxy group,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    5. The amide derivative of the above-mentioned 1, wherein R¹, R² and    R³ in the formula (1) are the same or different and each is hydrogen    atom, alkyl group having 2 to 4 carbon atoms or alkoxy group having    2 to 4 carbon atoms,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    6. The amide derivative of the above-mentioned 1, wherein R¹, R² and    R³ in the formula (1) are the same or different and each is hydrogen    atom, alkyl group having 2 to 4 carbon atoms or methoxy group,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    7. The amide derivative of the above-mentioned 1, wherein R⁴, R⁵ and    R⁶ in the formula (1) are the same or different and each is hydrogen    atom, alkyl group optionally having substituents, alkoxy group    optionally having substituents, acyloxy group optionally having    substituents, halogen atom, hydroxyl group, amino group, alkylamino    group, dialkylamino group, cyclic amino group, carboxyl group,    haloalkyl group or haloalkyloxy group,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    8. The amide derivative of the above-mentioned 1, wherein R⁴, R⁵ and    R⁶ in the formula (1) are the same or different and each is hydrogen    atom, alkyl group optionally having substituents, alkoxy group    optionally having substituents, acyloxy group optionally having    substituents, halogen atom, hydroxyl group, amino group, alkylamino    group, dialkylamino group, cyclic amino group, carboxyl group or    haloalkyl group,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    9. The amide derivative of the above-mentioned 1, wherein Z of the    formula (1) is —CH₂—,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    10. The amide derivative of the above-mentioned 1, wherein A of the    formula (1) is aryl group optionally having substituents or    heteroaryl group optionally having substituents,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    11. The amide derivative of the above-mentioned 1, wherein A of the    formula (1) is phenyl group optionally having substituents, pyridyl    group optionally having substituents, pyrazolyl group optionally    having substituents, thiazolyl group optionally having substituents,    oxazolyl group optionally having substituents or thienyl group    optionally having substituents,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    12. The amide derivative of the above-mentioned 1, wherein A of the    formula (1) is phenyl group optionally having substituents or a    nitrogen-containing heterocyclic group selected from the group    consisting of the following formulas (Aa)-(Ac)

wherein R¹⁰ is hydrogen atom, alkyl group optionally havingsubstituents, alkenyl group optionally having substituents, alkynylgroup optionally having substituents, cycloalkyl group, alkoxy groupoptionally having substituents, acyloxy group optionally havingsubstituents, halogen atom, hydroxyl group, nitro group, cyano group,acyl group, mercapto group, alkylthio group, alkylsulfonyl group, aminogroup, alkylamino group, dialkylamino group, cyclic amino group,carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group,oxadiazolyl group, sulfamoyl group or haloalkyl group,an optically active form thereof or a pharmaceutically acceptable saltthereof.13. The amide derivative of the above-mentioned 1, wherein X of theformula (1) is oxygen atom,an optically active form thereof or a pharmaceutically acceptable saltthereof.14. The amide derivative of the above-mentioned 1, wherein —W¹—Y—W²— ofthe formula (1) is —(CH₂)₂—, —(CH₂)₃— or —(CH₂)₂O—,an optically active form thereof or a pharmaceutically acceptable saltthereof.15. The amide derivative of any of the above-mentioned 1, wherein R¹, R²and R³ of the formula (1) are the same or different and each is hydrogenatom, alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to4 carbon atoms,a, b, c, d and e are each carbon atom, or either b or d is nitrogen atomand the rest are carbon atoms,R⁴, R⁵ and R⁶ are the same or different and each is hydrogen atom,methoxy group, halogen atom or hydroxyl group,Z is —CH₂—,A is phenyl group optionally having substituents or nitrogen-containingheterocyclic group selected from the group consisting of the followingformulas (Aa′)-(Ae′)

wherein R^(10a), R¹¹ and R¹² are the same or different and each ishydrogen atom, alkyl group optionally having substituents, cycloalkylgroup optionally having substituents, aryl group optionally havingsubstituents, heteroaryl group optionally having substituents, arylalkylgroup optionally having substituents, heteroarylalkyl group optionallyhaving substituents, alkoxy group optionally having substituents,aryloxy group, arylalkyloxy group, halogen atom, hydroxyl group, nitrogroup, cyano group, alkylthio group, amino group, alkylamino group,dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxygroup, R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)O— wherein j, k and l are eachindependently an integer of 2 to 10, R¹³ is hydrogen atom, alkyl groupoptionally having substituents, cycloalkyl group optionally havingsubstituents, aryl group optionally having substituents, heteroarylgroup optionally having substituents, arylalkyl group optionally havingsubstituents, heteroarylalkyl group optionally having substituents orhaloalkyl group, or R¹³O(CH₂)_(j)O(CH₂)_(k)O— wherein j, k and R¹³ areas defined above, R^(10b) is hydrogen atom, alkyl group optionallyhaving substituents, cycloalkyl group optionally having substituents,aryl group optionally having substituents, heteroaryl group optionallyhaving substituents, arylalkyl group optionally having substituents,heteroarylalkyl group optionally having substituents, haloalkyl group,haloalkyloxy group, R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)— wherein j, k, land R¹³ are as defined above, or R¹³O(CH₂)_(j)O(CH₂)_(k)— wherein j, kand R¹³ are as defined above,X is oxygen atom, and—W—Y—W²— is —(CH₂)₂— or —(CH₂)₃—,an optically active form thereof or a pharmaceutically acceptable saltthereof.16. The amide derivative of any of the above-mentioned 1 to 15, whereinthe amide derivative is selected from the group consisting of

-   N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)indan-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide,-   N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide,-   N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-carboxamide,-   N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    and-   N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-carboxamide,    an optically active form thereof or pharmaceutically acceptable salt    thereof.    17. The amide derivative of the above-mentioned 1, wherein the amide    derivative is-   N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    18. The amide derivative of any of the above-mentioned 1 to 15,    wherein the amide derivative is selected from the group consisting    of-   N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(6-dimethylaminopyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-ethoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-8-fluoro-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dimethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-ethoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-methylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl].    1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-bromophenyl)-N-[(dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-(2-tolylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(3-tolyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-tolyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dimethylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(2-methoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,6-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-ethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-oxachroman-6-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,3-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(2-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,4-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   8-fluoro-5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazole-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-heptylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-butylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-dodecylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-benzyloxy-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    and-   N-({1-[2-(2-ethoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    an optically active form thereof or a pharmaceutically acceptable    salt thereof.    19. A pharmaceutical composition comprising the amide derivative of    any of the aforementioned 1 to 18, an optically active form thereof    or a pharmaceutically acceptable salt thereof, and a    pharmaceutically acceptable additive.    20. A prophylactic or therapeutic drug of a disease, in which C5a is    involved, which comprises the amide derivative of any of the    aforementioned 1 to 18, an optically active form thereof or a    pharmaceutically acceptable salt thereof as an active ingredient.    21. The prophylactic or therapeutic drug of the aforementioned 20,    wherein the disease, in which C5a is involved, is an autoimmune    disease, sepsis, adult respiratory distress syndrome, chronic    obstructive pulmonary disease, an allergic disease, atherosclerosis,    cardiac infarction, brain infarction, psoriasis, Alzheimer's    disease, or serious organ injury due to activation of leukocytes    caused by ischemia reperfusion, trauma, burn or surgical invasion.    22. The prophylactic or therapeutic drug of the aforementioned 20,    wherein the disease, in which C5a is involved, is autoimmune    disease, sepsis, adult respiratory distress syndrome, an allergic    disease, atherosclerosis, cardiac infarction, brain infarction,    psoriasis, Alzheimer's disease, or serious organ injury due to    activation of leukocytes caused by ischemia reperfusion, trauma,    burn or surgical invasion.    23. A C5a receptor antagonist comprising the amide derivative of any    of the aforementioned 1 to 18, an optionally active form thereof or    a pharmaceutically acceptable salt thereof as an active ingredient.    24. The C5a receptor antagonist of the aforementioned 23, which is a    prophylactic or therapeutic drug of an infectious disease caused by    bacteria or virus that invades via the C5a receptor.    25. The C5a receptor antagonist of the aforementioned 23, which is    used in combination with an agent for the prophylaxis or treatment    of an autoimmune disease, sepsis, adult respiratory distress    syndrome, chronic obstructive pulmonary disease, an allergic    disease, atherosclerosis, cardiac infarction, brain infarction,    psoriasis, Alzheimer's disease, or serious organ injury due to    activation of leukocytes caused by ischemia reperfusion, trauma,    burn or surgical invasion.    26. A combination drug with an agent for the prophylaxis or    treatment of an autoimmune disease, sepsis, adult respiratory    distress syndrome, chronic obstructive pulmonary disease, an    allergic disease, atherosclerosis, cardiac infarction, brain    infarction, psoriasis, Alzheimer's disease, or serious organ injury    due to activation of leukocytes caused by ischemia reperfusion,    trauma, burn or surgical invasion, which comprises the amide    derivative of any of the aforementioned 1 to 18, an optionally    active form thereof or a pharmaceutically acceptable salt thereof as    an active ingredient.

MODE OF EMBODIMENT OF THE INVENTION

Some of the terms to be used in the present specification are defined asfollows.

The “substances that bind to a C5a receptor” means C5a, a hydrolysatesof C5a (e.g., C5a desArg wherein the carboxy terminal arginine of C5ahas been deleted), and known or unknown substances, which are other thanC5a, having affinity for C5a receptor.

The “C5a receptor antagonist” are substances that inhibit the bondbetween a C5a receptor and “substances that bind to a C5a receptor”.

The “C5a receptor antagonistic action” means an action that inhibits areaction that causes some physiological changes (e.g., increase ofintracellular Ca²⁺, and the like) by binding, via C5a receptor, of“substances that bind to a C5a receptor” to cells that express the C5areceptor.

In the present specification, each symbol is as defined in thefollowing.

In R¹-R¹³, R^(10a) and R^(10b), the alkyl group is straight chain orbranched chain alkyl having 1 to 18, preferably 1 to 12, carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondarybutyl, tertiary butyl, isopentyl, pentyl, 3-methylbutyl, neopentyl,1-ethylpentyl, hexyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl,dodecyl, hexadecyl, octadecyl and the like.

In R¹-R⁶ and R¹⁰, the alkenyl group is straight chain or branched chainalkenyl having 2 to 18, preferably 2 to 12, more preferably 2 to 8,carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl,3-butenyl, 2-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 5-hexenyl,4-methyl-3-pentenyl, 2-octenyl, 2-dodecenyl and the like.

In R¹-R⁶ and R¹⁰, the alkynyl group is straight chain or branched chainalkynyl having 2 to 18, preferably 2 to 12, more preferably 2 to 5,carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 5-pentynyl,2-octynyl, 2-dodecynyl and the like.

In R¹-R⁶, R¹⁰-R¹³, R^(10a), R^(10b) and A, the cycloalkyl group, forexample, is cycloalkyl preferably having 3 to 7 carbon atoms, such ascyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

In R¹-R⁶, R¹⁰-R¹² and R^(10a), the alkoxy group is, for example,straight chain or branched chain alkoxy having preferably 1 to 18 carbonatoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,secondary butoxy, tertiary butoxy, pentyloxy, 3-methylbutoxy,neopentyloxy, hexyloxy, heptyloxy, octyloxy, decyloxy, hexadecyloxy,octadecyloxy and the like, and the like.

In R¹-R⁶ and R¹⁰, the acyloxy group is, for example, alkanoyloxy having2 to 9 carbon atoms, such as acetoxy, propionyloxy, butyryloxy,isobutyryloxy, 2-methylbutyryloxy, 2,2-dimethylbutyryloxy,3,3-dimethylbutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy,heptanoyloxy, octanoyloxy, nonanoyloxy and the like,cycloalkylcarbonyloxy having 4 to 8 carbon atoms, such ascyclopentylcarbonyloxy, cyclohexylcarbonyloxy and the like,arylcarbonyloxy having 7 to 11 carbon atoms, such as benzoyloxy,naphthoyloxy and the like, and the like.

In R¹-R⁶, R¹⁰-R¹² and R^(10a), the halogen atom is chlorine, bromine,fluorine or iodine.

In R¹-R⁶ and R¹⁰, the acyl group is, for example, alkanoyl having 1 to8, preferably 2 to 8, carbon atoms, such as formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, octanoyl and thelike, cycloalkylcarbonyl having 4 to 8 carbon atoms (cycloalkyl moietyis same as the aforementioned cycloalkyl), such as cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like, aroyl having 7 to11 carbon atoms, such as benzoyl, toluoyl, naphthoyl and the like,heteroarylcarbonyl such as nicotinoyl, thenoyl, furoyl and the like, andthe like.

In R¹-R⁶, R¹⁰-R¹² and R^(10a), the alkylthio group is straight chain orbranched chain alkylthio having 1 to 18, preferably 1 to 12, carbonatoms, such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, secondary butylthio, tertiary butylthio,pentylthio, 3-methylbutylthio, neopentylthio, 1-ethylpentylthio,hexylthio, 2-ethylbutylthio, heptylthio, octylthio, decylthio,hexadecylthio, octadecylthio and the like.

In R¹-R⁶ and R¹⁰, the alkylsulfonyl group is alkylsulfonyl group whereinthe alkyl moiety is as defined for the above-mentioned “alkyl group”(straight chain or branched chain alkyl having 1 to 18, preferably 1 to12, carbon atoms). Examples thereof include methylsulfonyl group,ethylsulfonyl group, propylsulfonyl group and the like.

In R¹-R⁶, R¹⁰-R¹² and R^(10a), the alkylamino group is alkylamino groupwherein the alkyl moiety is as defined for the above-mentioned “alkylgroup”. Examples thereof include methylamino group, ethylamino group,propylamino group, isopropylamino group and the like.

In R¹-R⁶, R¹⁰-R¹² and R^(10a), the dialkylamino group is that whereineach alkyl moiety is as defined for the above-mentioned “alkyl group”and respective alkyl may be the same or different. Examples thereofinclude dimethylamino group, diethylamino group, dipropylamino group,diisopropylamino group, ethylmethylamino group, butylmethylamino groupand the like.

The cyclic amino group in R¹-R⁶, R¹⁰-R¹², R^(10a) and A is a 3 to8-membered saturated cyclic amino group that may contain one or moreoxygen atoms and sulfur atoms as ring-constituting atoms, besides carbonatom and nitrogen atom. Examples thereof include aziridinyl, azetidinyl,pyrrolizinyl, piperidino, piperidyl, piperazino, piperazinyl, azepinyl,morpholino, morpholinyl, thiomorpholinyl, imidazolidinyl,heptamethyleneimino and the like.

In R¹-R⁶, the sulfamoyl group is sulfamoyl group optionally mono- ordi-substituted with lower alkyl having 1 to 3 carbon atoms. Examplesthereof include sulfamoyl, methylsulfamoyl, ethylsulfamoyl,dimethylsulfamoyl and the like.

In R¹-R⁶, R¹⁰-R¹³, R^(10a) and R^(10b), the haloalkyl group is alkylsubstituted by one or more halogen atoms which is as the aforementioned“halogen atom”, wherein the alkyl moiety is as defined for theaforementioned “alkyl group”. Examples thereof include fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloromethyl,trichloromethyl and the like.

In the haloalkyloxy group for R⁴-R⁶, R¹¹, R¹², R^(10a) and R^(10b),“haloalkyl” is as defined for the aforementioned haloalkyl. Examples ofhaloalkyloxy group include trifluoromethyloxy, 2,2,2-trifluoroethyloxyand the like.

In R¹-R⁶, R¹¹-R¹³, R^(10a), R^(10b) and A, the aryl group is, forexample, aryl having 6 to 14 carbon atoms such as phenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 2-anthryl and the like. The aryl may have one ormore substituents wherein the position of substitution is notparticularly limited. The substituents may form a ring, may be condensedwith aryl and may be partially reduced.

In R¹-R⁶, R¹¹-R¹³, R^(10a), R^(10b) and A, the heteroaryl is a 5- to14-membered ring group that contains one or more hetero atoms such asnitrogen atom, oxygen atom, sulfur atom and the like asring-constituting atoms, besides carbon atom, may be monocyclic orpolycyclic and may be partially reduced. Examples thereof includepyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,indolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, phenazinyl, tetrazolyl, oxadiazolyl,imidazothienyl, 1,3-dioxaindanyl, 4-oxachromanyl and the like. Theseheteroaryl groups optionally have one or more substituents, where theposition of substitution is not particularly limited. In the case of apolycycle, any ring may be substituted. The bond may be present on anyring, if it is possible.

When any two of R¹, R² and R³ in combination with the adjacent carbonatom form a ring, it may be condensed with aryl (the “aryl” here is asdefined above), or partially reduced. In addition, the ring may containone or more hetero atoms such as nitrogen atom, oxygen atom, sulfur atomand the like to form heteroaryl (the “heteroaryl” here is as definedabove), and a ring wherein the heteroaryl is partially reduced is alsoencompassed.

In R¹-R⁶ and R¹⁰, the alkoxycarbonyl group is that wherein the alkoxymoiety is as defined for the above-mentioned “alkoxy group”. Thealkoxycarbonyl group is exemplified by methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,tertiary butoxycarbonyl group and the like.

In R¹-R⁶, the acylamino group is that wherein the acyl group is asdefined for the above-mentioned “acyl”. In addition, alkylsulfonylaminoand arylsulfonylamino are also encompassed in acylamino, wherein the“alkyl” and “aryl” here are as defined above. Examples of the acylaminogroup include acetamide, benzamide and the like.

In W¹, W² and Z, the alkylene group is alkylene having 1 to 10,preferably 1 or 2, carbon atoms. Examples thereof include methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,octamethylene, nonamethylene, decamethylene and the like.

In R¹-R⁶, R¹¹, R¹², R^(10a), R^(10b) and R¹³, the arylalkyl is thatwherein the aryl moiety is as defined for the aforementioned “arylgroup” and the alkyl moiety is straight chain or branched chain alkylhaving 1 to 12, preferably 1 to 3, carbon atoms. Examples of arylalkylinclude benzyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl,2-(1-naphthyl)ethyl, 2-naphthylmethyl, 2-(2-naphthyl)ethyl and the like.The aryl moiety of arylalkyl may have one or more substituents, wherethe position of substitution is not particularly limited.

In R¹-R⁶, R¹¹, R¹², R^(10a), R^(10b) and R¹³, the heteroarylalkyl groupis that wherein the heteroaryl moiety is as defined for theaforementioned “heteroaryl group” and the alkyl moiety is straight chainor branched chain alkyl having 1 to 12, preferably 1 to 3, carbon atoms.Examples of heteroarylalkyl include 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl,3-furylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl, 3-pyrazolylmethyl,4-pyrazolylmethyl, 5-pyrazolylmethyl, 2-imidazolylmethyl,4-imidazolylmethyl, 5-imidazolylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl, 5-oxazolylmethyl, 3-isoxazolylmethyl,4-isoxazolylmethyl, 5-isoxazolylmethyl, 2-thiazolylmethyl,4-thiazolylmethyl, 5-thiazolylmethyl, 3-isothiazolylmethyl,4-isothiazolylmethyl, 5-isothiazolylmethyl, 2-(2-pyridyl)ethyl,2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(2-thienyl)ethyl,2-(3-thienyl)ethyl, 2-(2-thiazolyl)ethyl, 2-(4-thiazolyl)ethyl,2-(5-thiazolyl)ethyl and the like. The heteroaryl moiety ofheteroarylalkyl group may have one or more substituents, where theposition of substitution is not particularly limited.

In R¹-R⁶, the carbamoyl group optionally having substituents is acarbamoyl group optionally mono or di-substituted by lower alkyl having1 to 3 carbon atoms. Examples thereof include carbamoyl,methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and the like.

In R¹-R⁶, R¹¹, R¹² and R^(10a), the aryloxy group is that wherein thearyl moiety is as defined for the aforementioned “aryl group”. Examplesof aryloxy group include phenoxy and the like.

In R¹-R⁶, R¹¹, R¹² and R^(10a), the arylalkyloxy group is that whereinthe arylalkyl moiety is as defined for the aforementioned “arylalkyl”.Examples of arylalkyloxy group include benzyloxy and the like.

In the present invention, specific examples of the substituent of the“optionally having substituents” include alkyl group, alkenyl group,alkynyl group, cycloalkyl group, aryl group, arylalkyl group, heteroarylgroup, heteroarylalkyl group, alkoxy group, aryloxy group, arylalkyloxygroup, acyloxy group, halogen atom, hydroxyl group, nitro group, cyanogroup, acyl group, mercapto group, alkylthio group, alkylsulfonyl group,amino group, alkylamino group, dialkylamino group, cyclic amino group,carbamoyl group, alkoxycarbonyl group, carboxyl group, acylamino group,sulfamoyl group, haloalkyl group, haloalkyloxy group, oxo group(provided that when it substitutes divalent nitrogen atom, it formsamine oxide), tetrahydropyran-2-yloxy,R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)O— wherein j, k, l and R¹³ are asdefined above, R¹³O(CH₂)_(j)O(CH₂)_(k)O— wherein j, k and R¹³ are asdefined above, R¹³O(CH₂)_(j)O— wherein j and R¹³ are as defined above,R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)— wherein j, k, l and R¹³ are asdefined above, R¹³O(CH₂)_(j)O(CH₂)_(k)— wherein j, k and R¹³ are asdefined-above, R¹³O(CH₂)_(j)— wherein j and R¹³ are as defined above),and the like, which are as defined above. These substituents may beoptionally substituted further by the substituents recited here. Inaddition, the substituted substituents are optionally substitutedfurther by the substituents recited here.

As the amide derivative (1), an optically active form thereof orpharmaceutically acceptable salt thereof of the present invention, forexample, amide derivative (1), wherein R¹, R² and R³ are the same ordifferent and each is hydrogen atom, alkyl group optionally havingsubstituents, alkenyl group optionally having substituents, alkynylgroup optionally having substituents, cycloalkyl group, alkoxy groupoptionally having substituents, acyloxy group optionally havingsubstituents, halogen atom, hydroxyl group, nitro group, cyano group,acyl group, mercapto group, alkylthio group, alkylsulfonyl group, aminogroup, alkylamino group, dialkylamino group, cyclic amino group,carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group,oxadiazolyl group, sulfamoyl group or haloalkyl group,

a, b, c, d and e are each carbon atom, or one or two of a, b, c, d and eis(are) nitrogen atom(s) and the rest are carbon atoms,

R⁴, R⁵ and R⁶ are the same or different and each is hydrogen atom, alkylgroup optionally having substituents, alkenyl group optionally havingsubstituents, alkynyl group optionally having substituents, cycloalkylgroup, alkoxy group optionally having substituents, acyloxy groupoptionally having substituents, halogen atom, hydroxyl group, nitrogroup, cyano group, acyl group, mercapto group, alkylthio group,alkylsulfonyl group, amino group, alkylamino group, dialkylamino group,cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxylgroup, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkylgroup,A is hydrogen atom, cycloalkyl group, aryl group optionally havingsubstituents, heteroaryl group optionally having substituents or cyclicamino group,W¹ and W² are the same or different and each is a bond or alkylene(C_(n)) optionally having substituents wherein n is an integer of 1 to3,X is oxygen atom or sulfur atom,Y is a bond, oxygen atom, —CO— and —N(R⁷)— wherein R⁷ is hydrogen atomor alkyl group optionally having substituents, —SO_(m)— wherein m is aninteger of 0 to 2, —CON(R⁸)— wherein R⁸ is hydrogen atom or alkyl groupoptionally having substituents, or —N(R⁹)CO— wherein R⁹ is hydrogen atomor alkyl group optionally having substituents, andZ is a bond or alkylene group optionally having substituents, anoptically active form thereof or a pharmaceutically acceptable saltthereof is preferable. At this time, a, b, c, d and e are preferably allcarbon atoms.

The R¹, R² and R³ of the formula (1) are preferably the same ordifferent and each is hydrogen atom, alkyl group having 2 to 4 carbonatoms or alkoxy group, more preferably hydrogen atom, alkyl group having2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms, stillmore preferably hydrogen atom, alkyl group having 2 to 4 carbon atoms ormethoxy group.

As R¹, preferred is alkyl group having 2 to 4 carbon atoms or alkoxygroup having 2 to 4 carbon atoms. As R² and R³, preferred is hydrogenatom.

As R⁴, R⁵ and R⁶ of the formula (1), preferred are the same or differentand each is hydrogen atom, alkyl group optionally having substituents,alkoxy group optionally having substituents, acyloxy group optionallyhaving substituents, halogen atom, hydroxyl group, amino group,alkylamino group, dialkylamino group, cyclic amino group, carboxylgroup, haloalkyl group or haloalkyloxy group, more preferred is hydrogenatom, alkyl group optionally having substituents, alkoxy groupoptionally having substituents, acyloxy group optionally havingsubstituents, halogen atom, hydroxyl group, amino group, alkylaminogroup, dialkylamino group, cyclic amino group, carboxyl group orhaloalkyl group.

As A of the formula (1), preferred is aryl group optionally havingsubstituents or heteroaryl group optionally having substituents, morepreferred is phenyl group optionally having substituents, pyridyl groupoptionally having substituents, pyrazolyl group optionally havingsubstituents, thiazolyl group optionally having substituents, oxazolylgroup optionally having substituents or thienyl group optionally havingsubstituents, still more preferred is phenyl group optionally havingsubstituents or nitrogen-containing heterocyclic group selected from thegroup consisting of the following formulas (Aa)-(Ac)

wherein R¹⁰ is hydrogen atom, alkyl group optionally havingsubstituents, alkenyl group optionally having substituents, alkynylgroup optionally having substituents, cycloalkyl group, alkoxy groupoptionally having substituents, acyloxy group optionally havingsubstituents, halogen atom, hydroxyl group, nitro group, cyano group,acyl group, mercapto group, alkylthio group, alkylsulfonyl group, aminogroup, alkylamino group, dialkylamino group, cyclic amino group,carbamoyl group, alkoxycarbonyl group, carboxyl group, tetrazolyl group,oxadiazolyl group, sulfamoyl group or haloalkyl group, or phenyl groupoptionally having substituents ora nitrogen-containing heterocyclic group selected from the groupconsisting of the following formulas (Aa′)-(Ae′)

wherein R^(10a), R¹¹ and R¹² are the same or different and each ishydrogen atom, alkyl group optionally having substituents, cycloalkylgroup optionally having substituents, aryl group optionally havingsubstituents, heteroaryl group optionally having substituents, arylalkylgroup optionally having substituents, heteroarylalkyl group optionallyhaving substituents, alkoxy group optionally having substituents,aryloxy group, arylalkyloxy group, halogen atom, hydroxyl group, nitrogroup, cyano group, alkylthio group, amino group, alkylamino group,dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxygroup, R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)O— wherein j, k, l and R¹³ areas defined above or R¹³O(CH₂)_(j)O(CH₂)_(k)O— wherein j, k and R¹³ areas defined above, R^(10b) is hydrogen atom, alkyl group optionallyhaving substituents, cycloalkyl group optionally having substituents,aryl group optionally having substituents, heteroaryl group optionallyhaving substituents, arylalkyl group optionally having substituents,heteroarylalkyl group optionally having substituents, haloalkyl group,R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)— wherein j, k, l and R¹³ are asdefined above, or R¹³O(CH₂)_(j)O(CH₂)_(k)— wherein j, k and R¹³ are asdefined above.

As —W¹—Y—W²— of the formula (1), —(CH₂)₂—, —(CH₂)₃— or —(CH₂)₂O— ispreferable.

It is preferable that a, b, c, d and e of the formula (1) be preferablyall carbon atoms, or that b (or d) be nitrogen atom and the rest becarbon atoms.

The case where the R¹, R² and R³ of the formula (1) are the same ordifferent and each is hydrogen atom, alkyl group having 2 to 4 carbonatoms or alkoxy group having 2 to 4 carbon atoms,

a, b, c, d and e are each carbon atom, or either b or d is nitrogen atomand the rest are carbon atoms,

R⁴, R⁵ and R⁶ are the same or different and each is hydrogen atom,methoxy group, halogen atom or hydroxyl group,

Z is —CH₂—,

A is phenyl group optionally having substituents or anitrogen-containing heterocyclic group selected from the groupconsisting of the following formulas (Aa′)-(Ae′)

wherein R^(10a), R¹¹ and R¹² are the same or different and each ishydrogen atom, alkyl group optionally having substituents, cycloalkylgroup optionally having substituents, aryl group optionally havingsubstituents, heteroaryl group optionally having substituents, arylalkylgroup optionally having substituents, heteroarylalkyl group optionallyhaving substituents, alkoxy group optionally having substituents,aryloxy group, arylalkyloxy group, halogen atom, hydroxyl group, nitrogroup, cyano group, alkylthio group, amino group, alkylamino group,dialkylamino group, cyclic amino group, haloalkyl group, haloalkyloxygroup, R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)O— wherein j, k, 1 and R¹³ areas defined above or R¹³O(CH₂)_(j)O(CH₂)_(k)O— wherein j, k and R¹³ areas defined above, R^(10b) is hydrogen atom, alkyl group optionallyhaving substituents, cycloalkyl-group optionally having substituents,aryl group optionally having substituents, heteroaryl group optionallyhaving substituents, arylalkyl group optionally having substituents,heteroarylalkyl group optionally having substituents, haloalkyl group,haloalkyloxy group, R¹³O(CH₂)_(j)O(CH₂)_(k)O(CH₂)_(l)— wherein j, k, land R¹³ are as defined above or R¹³O(CH₂)_(j)O(CH₂)_(k)— wherein j, kand R¹³ are as defined above,X is oxygen atom, and—W¹—Y—W²— is —(CH₂)₂— or —(CH₂)₃— is particularly preferable.

As X of the formula (1), oxygen atom is preferable.

As —W¹—Y—W²— of the formula (1), —(CH₂)₂— or —(CH₂)₃— is preferable.

As Z of the formula (1), —CH₂— is preferable.

Preferable examples of the amide derivative (1) are as follows:

-   N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)indan-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide,-   N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide,-   N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-carboxamide,-   N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    and-   N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-carboxamide,    moreover,-   N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    and in addition,-   N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(6-dimethylaminopyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-ethoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-8-fluoro-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dimethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(4-ethoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-methylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-bromophenyl)-N-[(dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-(2-tolylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(3-tolyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-tolyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dimethylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(2-methoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,6-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-ethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-oxachroman-6-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,3-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2,4-dimethoxyphenyl)    methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(2-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(4-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,4-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridine-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   8-fluoro-5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-heptylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-butylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(1-dodecylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   5-benzyloxy-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,-   N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide,    and-   N-({1-[2-(2-ethoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide.

The pharmaceutically acceptable salt of the compound of the formula (1)is preferably exemplified by a salt with inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like, a salt with organic acid such as acetic acid,propionic acid, succinic acid, glycolic acid, lactic acid, malic acid,tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, ascorbic acid and the like, a salt with alkali metal (lithium,sodium, potassium and the like), a salt with alkaline earth metal(calcium, magnesium and the like), a salt with metal such as aluminumand the like, salt with organic base such as piperidine, piperazine,morpholine, diethanolamine, ethylenediamine and the like.

The present invention encompasses solvates (e.g., hydrate) of thecompound of the above-mentioned formula (1) or a salt thereof, prodrugmetabolized in vivo to be converted to the compound of the formula (1),and active metabolites of the compound of the formula (1).

The compound of the present invention further encompasses any form of anoptically pure enantiomer, a diastereomer and a mixture of these.

While the compound of the present invention can be produced by thefollowing methods, the production method is not limited to them. Themethods exemplified here may be used alone or in combination and aconventional method may be further combined. Where necessary, eachcompound is protected or deprotected by a conventional method.

The compound (1a) wherein X of the formula (1) is oxygen atom can beproduced by the following methods 1-3.

Method 1: Production Method 1 of Compound (1a)

wherein R¹, R², R³, R⁴, R⁵, R⁶, a, b, c, d, e, A, W¹, W², Y and Z are asdefined above.

For step 1, a known amidation method or peptide synthesis method and thelike can be used for example, the reaction is carried out in thepresence of a condensing agent (e.g., carbodiimide(N,N-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and the like),diphenylphosphorylazide, carbonyldiimidazole, 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent),2-chloro-N-methylpyridinium iodide-tributylamine system (MukaiyamaMethod), N-cyclohexylcarbodiimide-N′-methylpolystyrene and the like, inan inert solvent or without solvent at preferably from −20° C. to 80° C.In step 1, a deoxydation agent [e.g., organic base (e.g., triethylamine,N-methylmorpholine, pyridine, dimethylaniline and the like), inorganicbase (e.g., sodium hydrogencarbonate, potassium carbonate, sodiumhydroxide and the like)] and the like may be present. Generally, thereaction of step 1 is completed within 24 hr.

The compound (1a) in step 1 can be also produced by converting compound(3) to a different reactive derivative. When the reactive derivative ofcompound (3) is acid halide (e.g., acid chloride, acid bromide and thelike) or acid anhydride (e.g., symmetric acid anhydride, mixed acidanhydride of lower alkyl carbonate, mixed acid anhydride of alkylphosphate and the like), the reaction with compound (2) is generallycarried out in an inert solvent or without solvent at from −20° C. to80° C.

Furthermore, when what is called an active ester (4-nitrophenyl ester,4-chlorobenzyl ester, 4-chlorophenyl ester, pentafluorophenyl ester,succinimide ester, benzotriazole ester, 4-dimethylsulfonium phenyl esterand the like) is used as the reactive derivative of compound (3), thereaction is generally carried out in an inert solvent or without solventat a temperature of from −20° C. to the refluxing temperature of thesolvent.

The inert solvent to be used in the aforementioned amidation isexemplified by hydrocarbons such as hexane, benzene, toluene, xylene andthe like, halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane and the like, ethers such as tetrahydrofuran (hereinafterto be abbreviated as THF), dioxane and the like, esters such as ethylacetate and the like, ketones such as acetone, methyl ethyl ketone andthe like, alcohols such as methanol, ethanol, isopropyl alcohol and thelike, amides such as N,N-dimethylformamide (hereinafter to beabbreviated as DMF), dimethylacetamide (hereinafter to be abbreviated asDMA) and the like, acetonitrile, dimethyl sulfoxide, water and a mixedsolvent thereof and the like.

Method 2: Production Method 2 of Compound (1a)

wherein R¹, R², R³, R⁴, R⁵, R⁶, a, b, c, d, e, A, W¹, W², Y and Z are asdefined above, and L is a leaving group such as halogen atom,methanesulfonyoxy or para-toluenesulfonyloxy and the like.

The compound (1a) can be produced by reacting compound (4) with compound(5).

In step 2, the reaction is carried out in a solvent that does notinhibit the reaction, in the presence of a deoxydation agent [e.g.,organic base (e.g., triethylamine, N-methylmorpholine, pyridine,dimethylaniline and the like), inorganic base (e.g., sodium hydride,sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and thelike)] and the like at from −20° C. to the refluxing temperature of thesolvent. The solvent to be used in step 2 is exemplified by hydrocarbonssuch as hexane, benzene, toluene and the like, halogenated hydrocarbonssuch as chloroform, dichloromethane, dichloroethane and the like, etherssuch as THF, dioxane and the like, esters such as acetic acid ester andthe like, ketones such as acetone, methyl ethyl ketone and the like,alcohols such as methanol, ethanol, isopropyl alcohol and the like,amides such as DMF, DMA and the like, acetonitrile, DMSO, water or amixed solvent thereof and the like.

Method 3: Production Method 3 of Compound (1a)

wherein R¹, R², R³, R⁴, R⁵, R⁶, a, b, c, d, e, A, W¹, W², Y and Z are asdefined above, and Hal is iodine atom, bromine atom or chlorine atom.

By reacting compound (7) with compound (6), compound (1a) can beproduced.

Step 3 is carried out in a solvent that does not inhibit the reaction inthe presence of a deoxydation agent such as an organic base (e.g.,triethylamine, N-methylmorpholine, pyridine, dimethylaniline and thelike) or an inorganic base (e.g., sodium hydride, sodiumhydrogencarbonate, potassium carbonate, sodium hydroxide and the like)and, where necessary, a catalyst such as copper, copper iodide and thelike at a temperature from −20° C. to the refluxing temperature of thesolvent. The solvent to be used in step 3 is exemplified by hydrocarbonssuch as hexane, benzene, toluene and the like, halogenated hydrocarbonssuch as chloroform, dichloromethane, dichloroethane and the like, etherssuch as THF, dioxane and the like, esters such as acetic acid ester andthe like, ketones such as acetone, methyl ethyl ketone and the like,alcohols such as methanol, ethanol, isopropyl alcohol and the like,amides such as DMF, DMA and the like, nitrobenzene, acetonitrile, DMSO,water or a mixed solvent thereof and the like.

Method 4: Production Method of Compound (1b) Wherein X of the Formula(1) is Sulfur Atom

wherein R¹, R², R³, R⁴, R⁵, R⁶, a, b, c, d, e, A, W¹, W², Y and Z are asdefined above.

The compound (1b) can be produced from compound (1a) by theabove-mentioned routes (step 4).

Step 4 is carried out in a solvent that does not inhibit the reaction inthe presence of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide(Lawesson's reagent), diphosphorus pentasulfide and the like.

The solvent to be used in step 4 is exemplified by benzene, toluene,xylene, THF, pyridine and the like. The reaction is carried out at atemperature of generally from 0° C. to the refluxing temperature of thesolvent. While the reaction time varies depending on the reactiontemperature, it is generally 1 hr-24 hr.

Method 5: Production Method of Compound (9) Wherein R⁴ of the Formula(1) is Hydroxyl Group and R⁵ and R⁶ are Hydrogen Atoms

wherein R¹, R², R³, a, b, c, d, e, A, W¹, W², X, Y and Z are as definedabove, and M is a hydroxyl-protecting group.

The compound (9) can be produced by eliminating the protecting group Mof compound (8) (step 5).

The protecting group M is exemplified by methyl, benzyl, substitutedbenzyl, benzyloxycarbonyl and the like.

The protecting group can be eliminated by a conventional method such ashydrolysis, acid treatment, hydrogenolysis with metal catalyst(palladium carbon, Raney-nickel and the like), depending on the kind ofthe protecting group, and the like.

Synthetic Method of Starting Material Compound

The compound (2) to be the starting material of method 1 can be producedby the following methods 6-8.

Method 6: Production Method of Compound (2)

wherein T is amino-protecting group such as acetyl, t-butoxycarbonyl andthe like and R¹, R², R³, a, b, c, d, e, A, Z and L are as defined above.

The compound (10) and compound (5) are reacted in a suitable solvent inthe presence of a base to give compound (11), and then a protectinggroup is eliminated to give compound (2) (steps 6 and 7).

The solvent to be used in step 6 is exemplified by methanol, ethanol,propanol, isopropyl alcohol, methylene chloride, chloroform, THF,dioxane, benzene, toluene, xylene, DMF, DMSO and the like. The base tobe used is exemplified by sodium hydride, sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate, sodium hydroxide, potassiumhydroxide, triethylamine, diisopropylethylamine, pyridine and the like.While the reaction temperature varies depending on the solvent, it isgenerally 0° C.-140° C., and while the reaction time varies depending onthe reaction temperature, it is generally from 1 hr to 24 hr.

This reaction can be also carried out without the protecting group T(when T is hydrogen atom), whereby compound (2) can be produced.

In step 7, the protecting group can be eliminated by a conventionalmethod such as hydrolysis, acid treatment and the like according to aconventional method, depending on the kind of the protecting group.

Method 7: Production Method of Compound (15), Wherein, in Compound (2),—Z—A is —CH(R¹¹)—U—A (U is Alkylene Optionally Having Substituents, R¹¹is Hydrogen Atom, Alkyl Optionally Having Substituents, Aryl orHeteroaryl, and A is as Defined Above

wherein R¹, R², R³, a, b, c, d, e, A, R¹¹ and U are as defined above.

The compound (12) and compound (13) are subjected to dehydrationcondensation without solvent or in a suitable solvent to give compound(14), which compound is then reduced in a suitable solvent, wherebycompound (15) can be produced (steps 8 and 9).

The dehydration condensation reaction of compound (12) and compound (13)in step 8 can be carried out in the presence of a dehydrating agent orby removing the generated water from the reaction system with Dean-Starktrap.

As the dehydrating agent to be used for this reaction, a conventionaldehydrating agent can be used. Examples of the dehydrating agent includeanhydrous magnesium sulfate, molecular sieves and the like. The solventto be used for the reaction may be, for example, methylene chloride,chloroform, benzene, toluene, xylene and the like. While the reactiontemperature varies depending on the solvent, it is generally from 0° C.to 150° C., and while the reaction time varies depending on the reactiontemperature, it is generally 1 hr-24 hr.

The reducing agent to be used for step 9 is exemplified by sodiumborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride,formic acid, sodium formate and the like. When sodiumtriacetoxyborohydride or sodium cyanoborohydride is used as a reducingagent, removal of water using the dehydrating agent or Dean-Stark trapin step 8 can be omitted. The solvent to be used for the reactionincludes, for example, water, methanol, ethanol, propanol, THF, dioxane,1,2-dichloroethane, acetic acid and the like, and a mixed solventthereof may be used. While the reaction temperature varies depending onthe solvent, it is generally from 0° C. to 80° C., and while thereaction time varies depending on the reaction temperature, it isgenerally from 1 hr to 24 hr.

Method 8: Production Method of Compound (18), Wherein, in Compound (2),—Z—A is —CH₂—U—A Wherein A and U are as Defined Above

wherein R¹, R², R³, a, b, c, d, e, A and U are as defined above.

The compound (12) or a salt thereof and compound (16) or a reactivederivative thereof are reacted without solvent or in a suitable solventto give compound (17), which compound is then reacted with a reducingagent in a suitable solvent, whereby compound (18) can be produced(steps 10 and 11).

The reaction of compound (12) or a salt thereof with compound (16) instep 10 can be carried out in the same manner as in step 1.

The reducing agent to be used for reduction in step 11 is exemplified bylithium aluminum hydride, borane and the like. The solvent to be usedfor reduction is, for example, THF, diethyl ether, hexane and the like;or a mixed solvent thereof. While the reaction temperature variesdepending on the solvent, it is generally from 0° C. to 65° C., andwhile the reaction time varies depending on the reaction temperature, itis generally from 1 hr to 24 hr.

The compound (3) to be the starting material can be produced by thefollowing methods 9-10.

Method 9: Production Method 1 of Compound (3)

The compound (3) to be used in Method 1 can be produced from compound(19) wherein R¹, R⁵, R⁶, W¹, W² and Y are as defined above according tothe method described in a reference (Synthetic Communications, 12(10),763-770, 1982) (step 12).

Method 10: Production Method 2 of Compound (3)

wherein R⁴, R⁵, R⁶, W¹, W², Y and L are as defined above.

The compound (3) can be produced from compound (19) via steps 13-16.

The reducing agent to be used for the reduction in step 13 is, forexample, lithium aluminum hydride, sodium borohydride, lithiumborohydride, diborane and the like. The solvent to be used in step 13is, for example, water, methanol, ethanol, propanol, ether, THF,dioxane, acetic acid and the like, or a mixed solvent thereof. While thereaction temperature varies depending on the solvent, it is generallyfrom 0° C. to 80° C., and while the reaction time varies depending onthe reaction temperature, it is generally from 1 hr to 24 hr.

When L of compound (21) in step 14 is chlorine atom, the reaction isgenerally carried out in an inert solvent or without solvent in thepresence of thionyl chloride, methanesulfonyl chloride,para-toluenesulfonyl chloride or triphenylphosphine, as necessary, inthe co-presence of an organic base such as triethylamine and the like,at from −20° C. to 80° C. The solvent to be used then is, for example,methylene chloride, chloroform, carbon tetrachloride, ether, DMF and thelike; or a mixed solvent thereof and the like.

When L of compound (21) is methanesulfonyoxy or para-toluenesulfonyloxy,the reaction is generally carried out in an inert solvent or withoutsolvent in the presence of methanesulfonyl chloride orpara-toluenesulfonyl chloride in the co-presence of an organic base suchas triethylamine and the like at from −20° C. to 80° C. The solvent isto be used here is, for example, methylene chloride, chloroform, ether,DMF or a mixed solvent thereof and the like.

The step 15 is carried out in a solvent that does not inhibit thereaction in the presence of sodium cyanide, potassium cyanide,tetraethylammonium cyanide and the like at a temperature of from −20° C.to the refluxing temperature of the solvent. The solvent to be used instep 15 includes water, ethanol, ethanol, propanol, ether, DMF, DMSO,acetone, acetonitrile and a mixed solvent and the like.

The step 16 is carried out in a solvent that does not inhibit thereaction in the presence of an inorganic base (e.g., sodium hydroxide,potassium hydroxide, barium hydroxide and the like) or an acid (e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid and the like) at atemperature of from −20° C. to the refluxing temperature of the solvent.The solvent to be used in step 16 is, for example, water, methanol,ethanol, propanol, ethylene glycol, ethylene glycol monomethyl ether,DME, acetic acid, formic acid; or a mixed solvent thereof and the like.

Method 11: Production Method of Compound (4), which is a StartingMaterial of Method 2

wherein R¹, R², R³, R⁴, R⁵, R⁶, a, b, c, d, e, W¹, W² and Y are asdefined above.

The compound (4) can be produced from compound (12) and compound (3).

That is, compound (4) can be produced by reacting compound (12) or asalt thereof with compound (3) or a reactive derivative thereof withoutsolvent or in a suitable solvent (step 17).

The reaction of compound (3) with compound (12) or a salt thereof instep 17 can be carried out in the same manner as in step 1.

Method 12: Production Method of Compound (7), which is a StartingMaterial of Method 3

wherein R⁴, R⁵, R⁶, A, W¹, W², Y and Z are as defined above.

The compound (7) can be produced by reacting compound (3) with compound(23) or a salt thereof (step 18).

That is, by reacting compound (23) or a salt thereof and compound (3) ora reactive derivative thereof without solvent or in a suitable solvent,compound (7) can be produced.

The reaction of compound (3) and compound (23) or a salt thereof in step18 can be carried out in the same manner as in step 1.

The product obtained in each of the above-mentioned steps can beisolated and purified by a conventional method.

A part of the compounds of the formula (1) in the present invention canbe converted to a salt as necessary by a treatment in a suitable solvent(methanol, ethanol and the like), with an acid (hydrochloric acid,sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid,methanesulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid,benzoic acid, citric acid, malic acid, mandelic acid,para-toluenesulfonic acid, acetic acid, succinic acid, malonic acid,lactic acid, salicylic acid, gallic acid, picric acid, carbonic acid,ascorbic acid, trifluoroacetic acid, tartaric acid and the like), analkali metal (lithium, sodium, potassium and the like), alkaline earthmetal (calcium, magnesium and the like), metal such as aluminum and thelike, or an organic base (piperidine, piperazine, morpholine,diethanolamine, ethylenediamine and the like).

When the crystal of obtained the compound of the present invention isnot a solvate and the like, the compound of the present invention can beconverted to a solvate by treating the compound with water,water-containing solvent or other solvent.

The compound of the formula (1) of the present invention, apharmaceutically acceptable salt thereof and a solvate thereof show aC5a receptor antagonistic action and are useful as a prophylactic ortherapeutic drug of diseases, in which C5a is involved, for example,diseases or syndromes due to inflammation caused by C5a [e.g.,autoimmune diseases such as rheumatism and systemic lupus erythematosusand the like; sepsis; adult respiratory distress syndrome; chronicobstructive pulmonary disease; allergic diseases such as asthma and thelike; atherosclerosis; cardiac infarction; brain infarction; psoriasis;Alzheimer's disease; serious organ injury (e.g., pneumonia, nephritis,hepatitis and pancreatitis and the like) due to activation of leukocytescaused by ischemia reperfusion, trauma, burn, surgical invasion, and thelike. In addition, they are useful as a prophylactic or therapeutic drugof infectious diseases due to bacteria or virus that invades via a C5areceptor.

When the compound of the present invention of the formula (1),pharmaceutical acceptable salt thereof and solvate thereof are used forthe aforementioned prophylaxis or treatment, it is generallyadministered systemically or topically and orally or parenterally. Thedose to patients varies depending on the age, body weight, sex, generalhealth conditions, treatment effect, diet, administration time,administration method, clearance rate, combination of drugs, thecondition of the disease under treatment and the like. It is generallydesirably in the range of from 0.1 mg to 500 mg per dose for an adult byoral administration once to several times a day, or in the range of from0.01 mg to 200 mg per dose for an adult by parenteral administration(preferably intravenous administration) once to several times a day.

Because the dose may change depending on various conditions as mentionedabove, when a dose smaller than the above-mentioned range may besufficient, a dose outside the above-mentioned range may be necessary.

The compound of the formula (1) of the present invention, apharmaceutically acceptable salt thereof and a solvate thereof can beused orally or parenterally, for example, by inhalation, rectaladministration, topical administration and the like as a pharmaceuticalcomposition or preparation (e.g., powder, granule, tablet, pill,capsule, syrup, elixir, suspension, solution and the like), wherein atleast one compound of the present invention can be used alone or usedupon admixing with a pharmaceutically acceptable carrier (excipient,binder, disintegrant, corrigent, corrective, emulsifier, diluent and/ordissolution aids and the like).

A pharmaceutical composition can be prepared according to a generalmethod. In the present specification, by the parenteral is meantsubcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection, drip and the like. A composition forinjection, such as sterile suspension for injection and oil suspensioncan be prepared using a suitable dispersing agent, wetting agent, orsuspending agent according to a method known in the art.

A solid composition for oral administration is exemplified by tablet,pill, capsule, powder, granule and the like. In the above-mentionedsolid composition, one or more active compounds can be admixed with atleast one additive such as sucrose, lactose, mannitol, maltitol,glucose, cornstarch, talc, hydroxypropylcellulose, microcrystallinecellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate,dextran, starches, agar, arginates, chitins, chitosans, pectins,tragacanth gums, Acacia, gelatins, collagens, casein, albumin, syntheticor semi-synthetic polymers or glicerides.

In addition, the above-mentioned composition can contain furtheradditives such as lubricants (e.g., magnesium stearate etc.),preservatives (e.g., parabens, sorbins etc.), antioxidants (e.g.,ascorbic acid, α-tocopherol, cysteine etc.), disintegrants (e.g.,carmellose calcium etc.), stabilizers (e.g., lactose etc.), dissolutionaids (e.g., glutamic acid, aspartic acid etc.), binder, thickener,sweetener, flavor, perfume and the like.

Where necessary, the tablet and pill may be coated with a film ofgastric or enteric coating such as sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and thelike, or may be coated with two or more layers. In addition, they mayinclude a capsule of absorbable material such as gelatin.

The liquid composition for oral administration includes pharmaceuticallyacceptable solution, suspension, syrup, elixir and the like, and maycontain a generally used inactive diluent (purified water, ethanol).This composition may contain, besides the inactive diluent, auxiliariessuch as wetting agent, suspending agent, sweetening agent, flavor,perfume and preservative. Other compositions for oral administrationare, for example, spray agent containing one or more active substancesand formulated by a method known per se.

The composition for injection for parenteral administration may includesterile aqueous or non-aqueous solution, suspension and emulsion.Examples of the aqueous solution and suspension include distilled waterfor injection and physiological saline. Examples of the water insolublesolution and suspension include propylene glycol, polyethylene glycol,olive oil, ethanol, polysorbate 80 and the like. The above-mentionedcomposition may further contain auxiliaries such as preservative,wetting agent, emulsifier, dispersing agent, stabilizer (e.g., lactoseand the like) and dissolution aids (e.g., amino acid such as arginine,glutamic acid, aspartic acid, and the like). These can be sterilized by,for example, filtration through a bacteria-retaining filter, addition ofmicrobicide or irradiation.

The composition for injection can be used by producing a sterile solidcomposition and dissolved, for example, the lyophilized product insterile water or sterile solvent for injection before use.

Other composition for parenteral administration include externalsolution, ointment, liniment, suppository and the like, containing oneor more active substances and formulated by a conventional method.

The suppository for rectal administration can be produced by admixingthe drug and a suitable non-irritant vehicle, which is a substance whichis solid at ambient temperature but liquid at the temperature ofintestine and which melts in the rectum to release the drug, such ascocoa butter and polyethylene glycols.

The amide derivative (1), an optically active form thereof or apharmaceutically acceptable salt thereof of the present invention areuseful as an active ingredient of a C5a receptor antagonist, which C5areceptor antagonist can be used as a drug for the prophylaxis ortreatment of infectious diseases caused by bacteria or viruses thatinvade via a C5a receptor, and can be used in combination with aprophylactic or therapeutic drugs of autoimmunity disease, sepsis, adultrespiratory distress syndrome, chronic obstructive pulmonary disease,allergic disease, atherosclerosis, cardiac infarction, cerebralinfarction, psoriasis, Alzheimer's disease, or serious organ injury dueto activation of leucytes caused by ischemia reperfusion, externalinjuries, burn or surgical invasion.

The compound of the formula (1) of the present invention, opticallyactive form thereof or a pharmaceutically acceptable salt thereof isexpected to show a superior treatment effect by a combined use with anagent for the prophylaxis or treatment of autoimmune diseases such asrheumatism, systemic lupus erythematosus and the like; sepsis; adultrespiratory distress syndrome; chronic obstructive pulmonary disease;allergic diseases such as asthma and the like; atherosclerosis; cardiacinfarction; brain infarction; psoriasis; Alzheimer's disease; or seriousorgan injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis andthe like) due to activation of leukocytes caused by ischemiareperfusion, trauma, burn, surgical invasion and the like. As usedherein, by the “combined use” is meant a combination composition of thecompound of the present invention or a pharmaceutically acceptable saltthereof with an agent for the prophylaxis or treatment of autoimmunediseases such as rheumatism, systemic lupus erythematosus and the like;sepsis; adult respiratory distress syndrome; chronic obstructivepulmonary disease; allergic diseases such as asthma and the like;atherosclerosis; cardiac infarction; brain infarction; psoriasis;Alzheimer's disease; or serious organ injury (e.g., pneumonia,nephritis, hepatitis, pancreatitis and the like) due to activation ofleukocytes caused by ischemia reperfusion, trauma, burn surgicalinvasion and the like, and the use as a potentiator of an action of anagent for the prophylaxis or treatment of autoimmune diseases such asrheumatism, systemic lupus erythematosus and the like; sepsis; adultrespiratory distress syndrome; chronic obstructive pulmonary disease;allergic diseases such as asthma and the like; atherosclerosis; cardiacinfarction; brain infarction; psoriasis; Alzheimer's disease; or seriousorgan injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis andthe like) due to activation of leukocytes caused by ischemiareperfusion, trauma, burn, surgical invasion and the like, includingcombined use and concurrent use, wherein two or more active ingredientcompounds are simultaneously used or used in a staggered manner with orwithout mixing. The pharmaceutical drug of the present invention whichis characterized by the combined use of the compound represented by theabove-mentioned formula (1), optically active form thereof or apharmaceutically acceptable salt thereof and an agent for theprophylaxis or treatment of autoimmune diseases such as rheumatism,systemic lupus erythematosus and the like; sepsis; adult respiratorydistress syndrome; chronic obstructive pulmonary disease; allergicdiseases such as asthma and the like; atherosclerosis; cardiacinfarction; brain infarction; psoriasis; Alzheimer's disease; or seriousorgan injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis andthe like) due to activation of leukocytes caused by ischemiareperfusion, trauma, burn, surgical invasion and the like is notparticularly limited in terms of the mode of use thereof as long as thecompound represented by the formula (1), optically active form thereofor a pharmaceutically acceptable salt thereof and an agent for theprophylaxis or treatment of autoimmune diseases such as rheumatism,systemic lupus erythematosus and the like; sepsis; adult respiratorydistress syndrome; chronic obstructive pulmonary disease; allergicdiseases such as asthma and the like; atherosclerosis; cardiacinfarction; brain infarction; psoriasis; Alzheimer's disease; or seriousorgan injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis andthe like) due to activation of leukocytes caused by ischemiareperfusion, trauma, burn, surgical invasion and the like are combined.For example, (A) the compound represented by the formula (1), opticallyactive form thereof or a pharmaceutically acceptable salt thereof, and(B) an agent for the prophylaxis or treatment of autoimmune diseasessuch as rheumatism, systemic lupus erythematosus and the like; sepsis;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; allergic diseases such as asthma and the like; atherosclerosis;cardiac infarction; brain infarction; psoriasis; Alzheimer's disease; orserious organ injury (e.g., pneumonia, nephritis, hepatitis,pancreatitis and the like) due to activation of leukocytes caused byischemia reperfusion, trauma, burn, surgical invasion and the like maybe formulated as preparations to be each generally administered, or acomposition wherein they are combined in advance may be used. Thecombined pharmaceutical drug of the present invention may be, forexample, a single agent obtained by mixing the compound represented bythe formula (1), optically active form thereof or a pharmaceuticallyacceptable salt thereof and an agent for the prophylaxis or treatment ofautoimmune diseases such as rheumatism, systemic lupus erythematosus andthe like; sepsis; adult respiratory distress syndrome; chronicobstructive pulmonary disease; allergic diseases such as asthma and thelike; atherosclerosis; cardiac infarction; brain infarction; psoriasis;Alzheimer's disease; or serious organ injury (e.g., pneumonia,nephritis, hepatitis, pancreatitis and the like) due to activation ofleukocytes caused by ischemia reperfusion, trauma, burn, surgicalinvasion and the like according to a known production method forpharmaceutical preparations using, where desired, pharmaceuticallyacceptable diluent, excipient and the like, or respective preparationsthereof obtained using, where desired, pharmaceutically acceptablediluent, excipient and the like, or a combination preparation in acontainer including respective preparations thereof (set, kit, pack).For example, the combined pharmaceutical drug of the present inventioncan be used as a combination preparation packaging the same or differentpreparations of a preparation containing the compound represented by theformula (1), optically active form thereof or a pharmaceuticallyacceptable salt thereof, and an agent for the prophylaxis or treatmentof autoimmune diseases such as rheumatism, systemic lupus erythematosusand the like; sepsis; adult respiratory distress syndrome; chronicobstructive pulmonary disease; allergic diseases such as asthma and thelike; atherosclerosis; cardiac infarction; brain infarction; psoriasis;Alzheimer's disease; or serious organ injury (e.g., pneumonia,nephritis, hepatitis, pancreatitis and the like) due to activation ofleukocytes caused by ischemia reperfusion, trauma, burn surgicalinvasion and the like, or as a composition containing the compoundrepresented by the formula (1), optically active form thereof or apharmaceutically acceptable salt thereof and an agent for theprophylaxis or treatment of autoimmune diseases such as rheumatism,systemic lupus erythematosus and the like; sepsis; adult respiratorydistress syndrome; chronic obstructive pulmonary disease; allergicdiseases such as asthma and the like; atherosclerosis; cardiacinfarction; brain infarction; psoriasis; Alzheimer's disease; or seriousorgan injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis andthe like) due to activation of leukocytes caused by ischemiareperfusion, trauma, burn surgical invasion and the like.

When the compound of the present invention, optically active formthereof or a pharmaceutically acceptable salt thereof is used as acombination composition, the ratio of the composition is optional, andthe amount of the compound of the present invention or apharmaceutically acceptable salt thereof to be mixed can be determineddepending on the kind of the various pharmaceutical agents to be mixedfor combination, and the factors such as titer and the like. When it isused as a combination drug, the dose of the compound of the presentinvention or a pharmaceutically acceptable salt thereof, and thepharmaceutical agent to be combined therewith can be determined asappropriate from the range generally employed. It is preferable toadminister in a smaller dose than the dose for single use of eachpharmaceutical agent, in the hope of affording a synergistic effect.

Examples of the agent for the prophylaxis or treatment of autoimmunediseases such as rheumatism, systemic lupus erythematosus and the like;sepsis; adult respiratory distress syndrome; chronic obstructivepulmonary disease; allergic diseases such as asthma and the like;atherosclerosis; cardiac infarction; brain infarction; psoriasis;Alzheimer's disease; or serious organ injury (e.g., pneumonia,nephritis, hepatitis, pancreatitis and the like) due to activation ofleukocytes caused by ischemia reperfusion, trauma, burn surgicalinvasion and the like include antirheumatic agents (gold compound,penicillamine, bucillamine, lobenzarit, actarit, salazosulfapyridineetc.), immunosuppressants (azathioprine, cyclophosphamide, methotrexate,brequinar sodium, deoxyspergualin, mizoribine, 2-morpholinoethylmycophenolate, cyclosporin, rapamycin, tacrolimus hydrate, leflunomide,OKT-3, anti-TNF-α antibody, anti-IL (interleukin)-6 antibody and FTY720(EP627406-B1) etc.), steroidal drugs (predonizolone,methylpredonizolone, dexamethazone, hydrocortizone etc.) or nonsteroidalanti-inflammatory agents (aspirin, indometacin, indometacin farnesylate,diclofenac sodium, alclofenac, amfenac sodium, ibuprofen, ketoprofen,loxoprofen sodium, naproxen, pranoprofen, zaltoprofen, mefenamic acid,flufenamic acid, tolfenamic acid, phenylbutazone, ketophenylbutazone,piroxicam, tenoxicam, ampiroxicam etc.), bactericides (gentamicin,tobramycin, cefotaxim, ceftazidime, vancomycin, erythromycin, imipenem,metronidazole etc.), cerebral circulatory metabolism improvers(meclofenoxate, idebenone, indeloxazine, nicergoline, propentofylline,cytochrome C, citicoline, ifenprodil, bencyclane, cinepazide, ozagrel,nizofenone, ibudilast, pentoxifylline, propentofylline, vinpocetine,brovincamine, dihydroergotoxine, moxisylyte, dilazep, nicardipine,cinnarizine, flunarizine, nilvadipine etc.), anti-platelet aggregationinhibitors (ticlopidine, aspirin, beraprost, dipyridamole, cilostazol,ozagrel, sarpogrelate etc.), anticoagulants (heparin, warfarin etc.),thrombolytic agents (urokinase, tissue plasminogen activator etc.),antiallergic agents (cromoglic acid, pranlukast, ozagrel, seratrodast,tranilast, amlexanox, repirinast, tazanolast, pemirolast, ibudilast,supratast, ketotifen, azelastine, oxatomide, terfenadine, mequitazine,epinastine, astemizole, ramatroban, zafirlukast etc.), proteolyticenzyme inhibitors (gabexate, nafamosutat, aprotinin etc.),acetylcholinesterase inhibitors (aricept etc.) and the like.

EXAMPLES

The present invention is specifically explained in the following byreferring to Preparation Examples, Examples, Formulation Examples andTest Examples, which are not to be construed as limitative.

¹H-NMR was measured at 300 MHz. The chemical shift of ¹H-NMR wasmeasured using tetramethylsilane (TMS) as the internal standard andexpressed as relative delta (δ) value in parts per million (ppm). Forthe coupling constant, obvious multiplicity is shown using s (singlet),d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), dd(double doublet), brs (broad singlet) and the like in hertz (Hz).

Thin-layer chromatography was manufactured by Merck, and columnchromatography was performed using silica gel manufactured by Fujisilysia chemical.

Preparation Example 1

To a solution of 4-dimethylaminobenzaldehyde (11 g) in toluene (200 mL)were added 4-isopropylaniline (10 g) and molecular sieves 4A (20 g)under ice-cooling, and the mixture was stirred at room temperature forone day. The molecular sieves 4A was filtered off from the reactionmixture, and the obtained filtrate was concentrated under reducedpressure. The residue was dissolved in methanol (200 mL) and sodiumborohydride (2.3 g) was added under ice-cooling. The mixture was stirredat room temperature for 5 hr. After methanol was distilled away, waterwas added to the residue, and the mixture was extracted with chloroform.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated to give(4-dimethylaminophenylmethyl)(4-isopropylphenyl)amine (13.6 g). meltingpoint: 71-73° C.

Preparation Example 2

By the reaction and treatment in the same manner as in PreparationExample 1 using 4-dimethylaminobenzaldehyde (10.0 g) and4-methoxyaniline (8.25 g) as a starting material,(4-dimethylaminophenylmethyl) (4-methoxyphenyl)amine (5 g) was obtained.melting point: 92-94° C.

Preparation Example 3

To a solution of 1-ethylpyrazole-4-carboxylic acid (2.34 g) in1,2-dichloroethane (50 mL) were added thionyl chloride (1.83 mL) andseveral drops of DMF, and the mixture was stirred at 70° C. for 1.5 hr.The reaction mixture was concentrated under reduced pressure, andmethylene chloride (20 mL) was added to the residue. To this solutionwas added a solution of 4-isopropylaniline (2.29 mL) in methylenechloride (20 mL) under ice-cooling. The temperature of the mixture wasraised to room temperature and stirred at the same temperature for 1 hr.The reaction mixture was added to saturated aqueous sodiumhydrogencarbonate and extracted with chloroform. The organic layer waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated, and ether and hexane were added to theresidue. The precipitated solid was collected by filtration to giveN-(4-isopropylphenyl)-1-ethylpyrazole-4-carboxamide (3.76 g) (meltingpoint: 141.0° C.). To this compound (3.75 g) was added borane-THFcomplex/1 mol/L-THF solution (BH₃.THF complex/1M THF solution) (29 mL)and the mixture was heated under reflux for 4 hr. After cooling thereaction mixture, 1 mol/L-hydrochloric acid (60 mL) was added, and themixture was stirred at room temperature for one day. The reactionmixture was added to saturated aqueous sodium hydrogencarbonate andextracted with chloroform. The organic layer was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated and the residue was purified by silica gel columnchromatography to give[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (1.95 g).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.47 (3H, t, J=7.3 Hz), 2.81(1H, sept, 6.9 Hz), 3.57-3.78 (1H, brs), 4.14 (2H, q, J=7.3 Hz), 4.15(2H, s), 6.62 (2H, d, J=8.4 Hz), 7.06 (2H, d, J=8.4 Hz), 7.36 (1H, s),7.47 (1H, s).

Preparation Example 4

6-Chloronicotinic acid (3.15 g), 4-isopropylaniline (2.73 mL) andtriethylamine (5.6 mL) were dissolved in DMF (150 mL).1-Hydroxybenzotriazole monohydrate (hereinafter to be abbreviated asHOBt.H₂O) (3.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (hereinafter to be abbreviated as WSCI.HCl) (4.03 g) wereadded under ice-cooling. The mixture was stirred at room temperature forone day and the reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated and etherwas added to the residue. The precipitated solid was collected byfiltration to give N-(4-isopropylphenyl)-6-chloropyridine-3-carboxamide(4.72 g).

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 2.91 (1H, sept, 6.9 Hz), 7.24(2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.52 (2H, d, J=8.4 Hz),7.72-7.87 (1H, m), 8.15 (1H, dd, J=2.4, 8.4 Hz), 8.84 (1H, d, J=2.4 Hz).

N-(4-Isopropylphenyl)-6-chloropyridine-3-carboxamide (1.00 g) wasdissolved in THF (10 mL) and sodium methoxide (0.21 g) was added. Themixture was stirred at 50° C. for one day. After cooling, the reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to giveN-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g).

A BH₃-THF complex/1M THF solution (6.3 mL) was added toN-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g), and themixture was heated under reflux for 4 hr. After cooling the reactionmixture, 1 mol/L hydrochloric acid (15 mL) was added and the mixture wasstirred at room temperature for one day. The reaction mixture was pouredinto saturated aqueous sodium hydrogencarbonate and extracted withchloroform. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give(4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.80 (1H, sept, 6.9 Hz),3.73-3.87 (1H, m), 3.93 (3H, s), 4.22 (2H, s), 6.59 (2H, d, J=8.4 Hz),6.72 (1H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4 Hz), 7.59 (1H, dd, J=2.4, 8.4Hz), 8.14. (1H, d, J=2.4 Hz).

Preparation Example 5

To a solution of 7-methoxytetralone (22.3 g) in nitromethane (5 mL) wasadded zinc iodide (0.65 g). While stirring the mixture, trimethylsilylcyanide (50 mL) was added under ice-cooling. The mixture was stirred atroom temperature for 1 hr, and the reaction mixture was partitionedbetween water and chloroform. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated and the residue was dissolved in a mixed solvent of aceticacid (200 mL) and conc. hydrochloric acid (200 mL). Thereto was addedstannous chloride (106 g) and the mixture was heated under reflux forone day. After cooling, the reaction mixture was extracted withchloroform. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and etherwas added to the residue. The precipitated solid was collected byfiltration to give 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (8.1 g). melting point: 126-127° C.

Preparation Example 6

By the reaction and treatment in the same manner as in PreparationExample 5 using 5-hydroxy-1-tetralone (20 g) as a starting material,5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (18.5 g) wasobtained. This compound (18.5 g) was dissolved in a mixed solvent of DMF(105 mL) and toluene (42 mL). Thereto were added benzyl bromide (25.8mL) and potassium carbonate (54 g), and the mixture was stirred at50-60° C. for 8 hr. The reaction mixture was partitioned between waterand ethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andmethanol (100 mL), 1,4-dioxane (100 mL) and 1 mol/L aqueous sodiumhydroxide solution (116 mL) were added to the residue. The mixture wasstirred at 50° C. for 5 hr. The reaction mixture was partitioned betweenwater and ethyl acetate, and the aqueous layer was acidified with conc.hydrochloric acid. The mixture was extracted with chloroform and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (20.4 g).melting point: 145-146° C.

Preparation Example 7

By the reaction and treatment in the same manner as in PreparationExample 5 using 4-chromanone (5.1 g) as a starting material,chroman-4-carboxylic acid (4.1 g) was obtained. melting point: 94.3° C.

Preparation Example 8

By the reaction and treatment in the same manner as in PreparationExample 5 using 6-methoxy-4-chromanone (6.1 g) as a starting material,6-methoxychroman-4-carboxylic acid (1.2 g) was obtained. melting point:97.4° C.

Preparation Example 9

By the reaction and treatment in the same manner as in PreparationExample 5 using 6-methoxy-1-indanone (5.6 g) as a starting material,6-methoxyindan-1-carboxylic acid (2.6 g) was obtained. melting point:101.1° C.

Preparation Example 10

By the reaction and treatment in the same manner as in PreparationExample 6 using 4-hydroxy-1-indanone (5 g) as a starting material,4-benzyloxyindan-1-carboxylic acid (1.4 g) was obtained. melting point:133.4° C.

Preparation Example 11

To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2 g)in methylene chloride (10 mL) was added thionyl chloride (1 mL) and themixture was heated under reflux with stirring for 3 hr. The reactionmixture was concentrated under reduced pressure, and THF (5 mL) wasadded to the residue. This solution was added to a solution of4-isopropylaniline (1.53 g) and triethylamine (4.6 mL) in THF (10 mL)under ice-cooling. The temperature was raised to room temperature, andthe mixture was stirred at the same temperature for 1 hr. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and hexane was added to the residue.The precipitated solid was collected by filtration to giveN-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.78g). melting point: 163.1° C.

Preparation Example 12

7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g),4-isopropylaniline (0.41 g) and triethylamine (0.84 mL) were dissolvedin DMF (20 mL), and HOBt.H₂O (0.48 g) and WSCI.HCl (0.61 g) were addedunder ice-cooling. The mixture was stirred at room temperature for oneday and the reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and etherwas added to the residue. The precipitated solid was collected byfiltration to giveN-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.70 g). melting point: 168-169° C.

Preparation Example 13

To a solution of ethyl pyrazole-4-carboxylate (13.0 g),4-dimethylaminopyridine (0.57 g) and triethylamine (15.5 mL) intetrahydrofuran (80 mL) was added a solution of di-tert-butyldicarbonate (24.3 g) in tetrahydrofuran (20 mL) at room temperature. Themixture was stirred at the same temperature for 4 hr. The reactionmixture was concentrated under reduced pressure, and the residue waspartitioned between water and ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was purified by silica gelcolumn chromatography to give ethyl1-(tert-butyloxycarbonyl)pyrazole-4-carboxylate (22.1 g).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.1 Hz), 1.67 (9H, s), 4.33 (2H, q,J=7.1 Hz), 8.06 (1H, s), 8.56 (1H, s).

Ethyl (1-tert-butyloxycarbonyl)pyrazole-4-carboxylate (17.0 g) wasdissolved in anhydrous tetrahydrofuran (150 mL), and 1 mol/Ldiisobutylaluminum hydride/toluene solution (142 mL) was added at −78°C. over 40 min. The reaction temperature was raised to 0° C. over 1.5hr, and methanol-ether (1:9) (100 mL), saturated aqueous potassiumsodium tartrate tetrahydrate (Rochelle salt) solution (70 mL), water(330 mL) and ether (1 L) were successively added to the reaction mixtureat the same temperature. The mixture was stirred for one more hour. Thereaction mixture was passed through Celite, and the filtrate was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (5.92 g).

¹H-NMR (CDCl₃) δ: 1.64 (9H, s), 4.61 (2H, s), 7.69 (1H, s), 8.03 (1H,s).

Preparation Example 14

By the reaction and treatment in the same manner as in PreparationExample 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (5.48 g) and 4-isopropylaniline (3.90 mL) as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(5.94 g) was obtained. melting point: 170.4° C.

Preparation Example 15

By the reaction and treatment in the same manner as in PreparationExample 11 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.51g) and 5-amino-2-isopropylpyridine (1.17 g) as starting materials,N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.18 g) was obtained. melting point: 155.7° C.

Preparation Example 16

By the reaction and treatment in the same manner as in PreparationExample 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (1.06 g) and 5-amino-2-isopropylpyridine (0.50 g) as startingmaterials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.08 g) was obtained. melting point: 157.4° C.

Preparation Example 17

By the reaction and treatment in the same manner as in PreparationExample 11 using5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(2.30 g) and 5-amino-2-isopropylpyridine (1.04 g) as starting materials,5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.83 g) was obtained. melting point: 184.0° C.

Preparation Example 18

To a solution of 8-nitrochroman-4-carboxylic acid (3.0 g) and4-isopropylaniline (2.0 g) in dimethylformamide (30 mL) were addedN-hydroxybenzotriazole hydrate (2.0 g) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g),and the mixture was stirred at room temperature. After the completion ofthe reaction, the reaction mixture was partitioned between water andethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography to giveN-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.20-2.40 (1H, m), 2.50-2.70(1H, m), 2.80-3.00 (1H, m), 3.80-3.95 (1H, m), 4.30-4.60 (2H, m),6.90-7.60 (7H, m), 7.75-7.90 (1H, m)

Preparation Example 19

By the reaction and treatment in the same manner as in PreparationExample 18 using 4-benzyloxyindan-1-carboxylic acid (0.8 g) and2,4-dimethoxyaniline (0.5 g) as starting materials,4-benzyloxy-N-(2,4-dimethoxyphenyl) indan-1-carboxamide (0.96 g) wasobtained. melting point: 129.7° C.

¹H-NMR (CDCl₃) δ: 2.40-2.60 (2H, m), 2.90-3.20 (2H, m), 3.75 (3H, s),3.78 (3H, s), 4.00-4.20 (1H, m), 5.12 (2H, s), 6.40-6.50 (2H, m), 6.82(1H, d, J=8.0 Hz), 7.01 (1H, d, J=7.5 Hz), 7.10-7.60 (6H, m), 7.73 (1H,brs), 8.24 (1H, d, J=8.6 Hz)

Preparation Example 20

By the reaction and treatment in the same manner as in PreparationExample 18 using5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(1.34 g) and 5-amino-2-isopropylpyridine (0.62 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.75 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=6.9 Hz), 1.55-1.80 (1H, m), 1.85-2.00(2H, m), 2.20 (3H, s), 2.40-2.55 (1H, m), 2.55-2.75 (1H, m), 2.95-3.10(2H, m), 3.80-3.90 (1H, m), 5.10 (2H, s), 6.83 (1H, d, J=8.1 Hz),7.00-7.50 (8H, m), 7.95-8.10 (1H, m), 8.27 (1H, d, J=2.4 Hz)

Preparation Example 21

By the reaction and treatment in the same manner as in PreparationExample 18 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (20.0 g) and 5-amino-2-methoxypyridine (8.72 g), as startingmaterials,5-benzyloxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(23.9 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.62-1.69 (1H, m), 1.96-2.05 (3H, m), 2.64-2.69 (2H,m), 3.82 (3H, s), 3.81-3.85 (1H, m), 5.11 (2H, s), 6.71-6.89 (3H, m),7.05-7.10 (1H, m), 7.30-7.49 (5H, m), 7.92-7.96 (1H, m), 8.39-8.40 (1H,m), 10.20 (1H, s)

Preparation Example 22

7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5.0 g) and(R)-(+)-1-phenethylamine (3.13 mL) were dissolved in methanol (50 mL),and the solvent was evaporated under reduced pressure to give crudecrystals (7.33 g). This was recrystallized from a mixed solvent ofmethanol and isopropyl ether. The obtained crystals were partitionedbetween ethyl acetate and 1 mol/L-hydrochloric acid. The organic layerwas washed with saturated brine and dried over magnesium sulfate.

The solvent was evaporated under reduced pressure to give(R)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.65 g).

optical purity>99.9% e.e.

Analysis Conditions

column: CHIRALCEL OD (DAICEL)

developing solvent: hexane/isopropanol/acetic acid=97/3/3

flow rate: 0.5 mL/min

UV detection: 254 nm

retention time: 21.5 min

Preparation Example 23

7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5.0 g) and(S)-(−)-1-phenethylamine (3.2 mL) were dissolved in methanol (50 mL),and the solvent was evaporated under reduced pressure to give crudecrystals (7.33 g). This was recrystallized from a mixed solvent ofmethanol and isopropyl ether. The obtained crystals were partitionedbetween ethyl acetate and 1 mol/L-hydrochloric acid. The organic layerwas washed with saturated brine and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure to give(S)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.96 g).

optical purity>99.9% e.e.

Analysis Conditions

column: CHIRALCEL OD (DAICEL)

developing solvent: hexane/isopropanol/acetic acid=97/3/3

flow rate: 0.5 mL/min

UV detection: 254 nm

retention time: 26 min

Preparation Example 24

By the reaction and treatment in the same manner as in PreparationExample 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (2.82 g) and 2-amino-5-methylpyridine (1.08 g) as startingmaterials,5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.00 g) was obtained.

MS (ESI) m/z: 373 [MH]⁺

Example 1

To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g)in methylene chloride (10 mL) was added thionyl chloride (0.68 mL), andthe mixture was heated under reflux with stirring for 3 hr. The reactionmixture was concentrated under reduced pressure, and THF (6 mL) wasadded to the residue. This solution was added to a solution of[(4-dimethylaminophenyl)methyl](4-ethylphenyl)-amine (1.2 g) andtriethylamine (2 mL) in THF (6 mL) under ice-cooling. The mixture wasallowed to warm to room temperature and stirred at the same temperaturefor one day. The reaction mixture was partitioned between water andethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was purified by silica gel column chromatography. Theobtained crystals were recrystallized from a mixed solvent of ethylacetate and hexane to giveN-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.28 g). melting point: 109-110° C.

Example 2

By the reaction and treatment in the same manner as in Example 1 usingindan-1-carboxylic acid (0.46 g) and[(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as startingmaterials, N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)indan-1-carboxamide (0.15 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.3 Hz), 2.00-2.20 (1H, m), 2.25-2.45(1H, m), 2.63 (2H, q, J=7.3 Hz), 2.65-2.85 (1H, m), 2.93 (6H, s),3.00-3.15 (1H, m), 3.96 (1H, t, J=7.9 Hz), 4.73 (1H, d, J=13.9 Hz), 4.94(1H, d, J=13.9 Hz), 6.64 (2H, d, J=8.6 Hz), 6.97 (2H, d, J=7.9 Hz),7.00-7.20 (8H, m).

Example 3

By the reaction and treatment in the same manner as in Example 1 using6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.54 g) and[(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as startingmaterials,N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxamide(0.2 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.17 (3H, t, J=7.3 Hz), 1.20-2.05 (6H, m), 2.10-2.30(1H, m), 2.56 (3H, q, J=7.3 Hz), 2.92 (6H, s), 3.69 (1H, d, J=7.9 Hz),4.78 (1H, d, J=13.9 Hz), 4.90 (1H, d, J=13.9 Hz), 6.55-6.65 (4H, m),6.90-7.30 (8H, m).

Example 4

To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (3.3 g)in 1,2-dichloroethane (20 mL) was added thionyl chloride (2.1 mL), andthe mixture was heated under reflux with stirring for 3 hr. The reactionmixture was concentrated under reduced pressure, and methylene chloride(10 mL) was added to the residue. This solution was added to a solutionof [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (5.1 g) inmethylene chloride (10 mL) under ice-cooling. The reaction mixture waswarmed to room temperature and stirred at the same temperature for oneday. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography. The obtainedcrystals were recrystallized from isopropyl ether to giveN-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(4.38 g) melting point: 121° C.

Example 5

To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.24g) in methylene chloride (3 mL) was added thionyl chloride (0.15 mL),and the mixture was heated under reflux with stirring for 3 hr. Thereaction mixture was concentrated under reduced pressure, and THF (2 mL)was added to the residue. This solution was added to a solution of(5-bromo-2-isobutoxyphenyl)[(4-dimethylaminophenyl)methyl]amine (0.5 g)and sodium hydride (0.07 g) in THF (3 mL). The reaction mixture waswarmed to room temperature and stirred at the same temperature for oneday. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography. The obtainedcrystals were recrystallized from ethyl acetate to giveN-(5-bromo-2-isobutoxyphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.3 g). melting point: 176-178° C.

Example 6

N-(4-Isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5g) and butyl bromide (0.22 mL) were dissolved in DMF (3 mL), and sodiumhydride (0.08 g) was added under ice-cooling. The mixture was stirred atthe same temperature for 30 min and then at room temperature for 3 hr.The reaction mixture was partitioned between water and ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas purified by silica gel column chromatography to giveN-butyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g).

¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J=7.3 Hz), 1.26 (6H, d, J=6.6 Hz),1.20-1.65 (5H, m), 1.80-2.10 (3H, m), 2.63 (1H, dt, J=16.5 Hz, 4.6 Hz),2.75-3.00 (2H, m), 3.65-3.80 (3H, m), 6.95-7.30 (8H, m).

Example 7

By the reaction and treatment in the same manner as in Example 6 usingN-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5g) and 2-morpholino-2-oxoethyl chloride (0.33 g) as starting materials,N-(4-isopropylphenyl)-N-(2-morpholino-2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) was obtained. melting point: 180° C.

Example 8

By the reaction and treatment in the same manner as in Example 6 usingN-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75g) and 3-(tetrahydropyran-2-yloxy)propyl bromide (0.52 mL) as startingmaterials,N-(4-isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.9 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=7.3 Hz), 1.40-2.10 (13H, m), 2.63 (1H,dt, J=16.5 Hz, 4.6 Hz), 2.75-3.05 (2H, m), 3.35-3.50 (2H, m), 3.70-4.00(4H, m), 4.12 (1H, dd, J=14.5 Hz, 7.3 Hz), 6.95-7.30 (8H, m).

Example 9

N-(4-Isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.24 g) was dissolved in a mixed solvent (7 mL) of acetic acid: THF:water (4:2:1) and stirred at room temperature for 2 hr. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography to giveN-(3-hydroxypropyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g).

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.6 Hz), 1.40-2.10 (6H, m), 2.65 (1H,dt, J=16.5 Hz, 4.6 Hz), 2.75-3.05 (2H, m), 3.60-3.90 (4H, m), 3.95-4.15(4H, m), 6.95-7.30 (8H, m).

Example 10

By the reaction and treatment in the same manner as in Example 1 usingthiochroman-4-carboxylic acid (0.55 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)thiochroman-4-carboxamide(0.3 g) was obtained. melting point: 118° C.

Example 11

By the reaction and treatment in the same manner as in Example 1 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.56 g) and(3-cyanopropyl) (4-isopropylphenyl)amine (1.79 g) as starting materials,N-(3-cyanopropyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.56 g) was obtained. melting point: 74-750° C.

Example 12

To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylicacid (1.0 g) in 1,2-dichloroethane (20 mL) was added thionyl chloride(2.1 mL), and the mixture was heated under reflux with stirring for 3hr. The reaction mixture was concentrated under reduced pressure, andmethylene chloride (10 mL) was added to the residue. This solution wasadded to a solution of[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.3 g) inmethylene chloride (10 mL) under ice-cooling. The reaction mixture waswarmed to room temperature and stirred at the same temperature for oneday. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography to giveN-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.73 g).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.3 Hz), 1.43-1.45 (1H, m), 1.86-2.01(2H, m), 2.25 (3H, s), 2.54-2.79 (1H, m), 2.70-3.00 (2H, m), 2.93 (6H,s), 3.68 (1H, t, J=8.6 Hz), 3.68 (3H, s), 4.59 (1H, d, J=14 Hz), 6.51(1H, d, J=2.5 Hz), 6.66 (2H, dd, J=2.6, 8.5 Hz), 6.91-6.99 (2H, m), 7.17(2H, dd, J=8.7, 14 Hz).

Example 13

By the reaction and treatment in the same manner as in Example 1 usingchroman-4-carboxylic acid (0.5 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) asstarting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.25 g) wasobtained. melting point: 110-112° C.

Example 14

By the reaction and treatment in the same manner as in Example 1 using1,1-dioxothiochroman-4-carboxylic acid (0.26 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.31 g) asstarting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,1-dioxothiochroman-4-carboxamide (0.07g) was obtained. melting point: 185-187° C.

Example 15

By the reaction and treatment in the same manner as in Example 12 using5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.48 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.3 Hz), 1.43-1.45 (1H, m), 1.86-2.01(2H, m), 2.25 (3H, s), 2.63 (1H, t, 5.9 Hz), 2.80-2.99 (1H, m),2.70-3.00 (2H, m), 2.94 (6H, s), 3.68 (1H, t, J=8.6 Hz), 3.77 (3H, s),4.73 (1H, d, J=14 Hz), 4.95 (1H, d, J=14 Hz), 6.66 (2H, d, J=8.0 Hz),6.68 (2H, s), 6.97 (2H, d, J=8.0 Hz), 7.04-7.30 (5H, m).

Example 16

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) asstarting materials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.3 Hz), 1.39-1.53 (1H, m), 1.79-2.08(3H, m), 2.68-2.78 (2H, m), 2.83-2.92 (1H, m), 2.94 (6H, s), 3.73 (1H,t, J=8.6 Hz), 4.72 (1H, d, J=14 Hz), 4.93 (1H, d, J=14 Hz), 5.03 (2H,s), 6.61-6.74 (4H, m), 6.94-7.20 (7H, m), 7.28-7.44 (5H, m).

Example 17

5-Benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) was dissolved in methanol (60 mL), and 10% palladium carbon(0.5 g) and ammonium formate (1.5 g) were added. The mixture was stirredat room temperature for one day. The reaction mixture was filtrated, andthe filtrate was concentrated. Water was added to the residue, and theprecipitated crude crystals were recrystallized from ethyl acetate togiveN-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g). melting point: 200-202° C.

Example 18

By the reaction and treatment in the same manner as in Example 1 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and(4-isopropylphenyl)[6-(tetrahydropyran-2-yloxy)hexyl]amine (2.0 g) asstarting materials,N-(4-isopropylphenyl)-N-[6-(tetrahydropyran-2-yloxy)hexyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.0 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 9,N-(6-hydroxyhexyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.64 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=7.3 Hz), 1.20-2.10 (13H, m), 2.63 (1H,dt, J=16.5 Hz, 4.6 Hz), 2.75-3.05 (2H, m), 3.59 (2H, t, J=5.9 Hz),3.65-3.80 (3H, m), 6.95-7.30 (8H, m).

Example 19

By the reaction and treatment in the same manner as in Example 1 using2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.5 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxamide(0.6 g) was obtained. melting point: 170° C.

Example 20

N-[(4-Dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(3.2 g) was dissolved in methylene chloride (60 mL), and borontribromide (0.72 mL) was added under ice-cooling. The mixture wasstirred at room temperature for one day. The reaction mixture waspartitioned between saturated aqueous sodium hydrogencarbonate andchloroform. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography to giveN-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g). melting point: 214-217° C.

Example 21

By the reaction and treatment in the same manner as in Example 12 using6-methoxyindan-1-carboxylic acid (0.5 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide(0.53 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.6 Hz), 2.00-2.20 (1H, m), 2.30-2.50(1H, m), 2.60-2.75 (1H, m), 2.80-3.10 (2H, m), 2.93 (6H, s), 3.74 (3H,s), 3.93 (1H, t, J=7.9 Hz), 4.68 (1H, d, J=13.9 Hz), 4.98 (1H, d, J=13.9Hz), 6.60-6.75 (4H, m), 6.90-7.20 (7H, m).

Example 22

By the reaction and treatment in the same manner as in Example 1 using7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.07 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-7-isopropyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g) was obtained. melting point: 123-125° C.

Example 23

By the reaction and treatment in the same manner as in Example 1 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.57 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g) was obtained. melting point: 75-76° C.

Example 24

By the reaction and treatment in the same manner as in Example 12 using6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.6 Hz), 1.35-1.55 (1H, m), 1.75-2.10(3H, m), 2.55-2.70 (1H, m), 2.75-3.00 (2H, m), 2.94 (6H, s), 3.60-3.70(1H, m), 3.74 (3H, s), 4.70 (1H, d, J=13.9 Hz), 4.93 (1H, d, J=13.9 Hz),6.50-6.75 (4H, m), 6.90-7.20 (7H, m).

Example 25

By the reaction and treatment in the same manner as in Example 1 using6-methoxychroman-4-carboxylic acid (0.54 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) asstarting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide (0.3 g) wasobtained. melting point: 82-84° C.

Example 26

By the reaction and treatment in the same manner as in Example 12 using7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl) amine (1.40 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.3 Hz), 1.43-1.45 (1H, m), 1.86-2.01(2H, m), 2.25 (3H, s), 2.54-2.79 (1H, m), 2.70-3.00 (2H, m), 2.93 (6H,s), 3.69 (1H, t, J=8.6 hz), 4.70 (1H, d, J=14 Hz), 4.98 (1H, d, J=14Hz), 6.65 (2H, d, J=8.5 Hz), 6.80 (1H, s), 6.91 (2H, s), 6.96 (2H, d,J=7.9 Hz), 7.15 (4H, dd, J=6.6, 8.6 Hz).

Example 27

By the reaction and treatment in the same manner as in Example 1 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and[(4-chlorophenyl)methyl](4-isopropylphenyl)amine (1.3 g) as startingmaterials, N-[(4-chlorophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.1 g) was obtained. melting point: 122-123° C.

Example 28

By the reaction and treatment in the same manner as in Example 1 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and[(4-chlorophenyl)methyl](4-isopropylphenyl) amine (1.5 g) as startingmaterials,N-[(4-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) was obtained. melting point: 87-88° C.

Example 29

By the reaction and treatment in the same manner as in Example 1 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and[(4-bromophenyl)methyl](4-isopropylphenyl)amine (2.21 g) as startingmaterials,N-[(4-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.526 g) was obtained. melting point: 85° C.

Example 30

By the reaction and treatment in the same manner as in Example 1 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and[(1,3-dioxaindan-5-yl)methyl](4-isopropylphenyl)amine (1.3 g) asstarting materials,N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.3 g) was obtained. melting point: 97-98° C.

Example 31

By the reaction and treatment in the same manner as in Example 1 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g) and[(4-cyanophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as startingmaterials,N-[(4-cyanophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.63 g) was obtained. melting point: 137-138° C.

Example 32

By the reaction and treatment in the same manner as in Example 1 using6-fluorochroman-4-carboxylic acid (1.96 g) and[(4-dimethylaminophenyl)methyl] (4-isopropylphenyl) amine (2.68 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-carboxamide(2.89 g) was obtained. melting point: 95-98° C.

Example 33

By the reaction and treatment in the same manner as in Example 4 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and[(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.65g) as starting materials,N-[(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained. Oxalic acid was added to this compound. Byrecrystallization from ethyl acetate,N-[(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide½ oxalate ½ hydrate (0.03 g) was obtained. melting point: 142-143° C.

Example 34

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and(4-isopropylphenyl)[(4-methylthiophenyl)methyl]amine (2.0 g) as startingmaterials,N-(4-isopropylphenyl)-7-methoxy-N-[(4-methylthiophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.4 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=7.3 Hz), 1.43-1.45 (1H, m), 1.86-2.01(3.H, m), 2.25 (3H, s), 2.47 (3H, s), 2.53-2.61 (1H, m), 2.71-2.97 (2H,m), 3.70 (3H, s), 3.72 (1H, t, J=8.6 Hz), 4.70 (1H, d, J=14 Hz), 5.04(1H, d, J=14 Hz), 6.65 (1H, d, J=2.7 Hz), 6.67 (1H, dd, J=2.7, 8.6 Hz),6.93-6.99 (3H, m), 7.16-7.22 (6H, m).

Example 35

N-(4-Isopropylphenyl)-7-methoxy-N-[(4-methylthiophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.0 g) was dissolved in acetic acid (10 mL), and 30% aqueous hydrogenperoxide (5.5 mL) was added at room temperature. The mixture was stirredwith heating at 100° C. for 3 hr. Water was added to the reactionmixture, and the precipitated solid was purified by silica gel columnchromatography to give crude crystals. The crystals were recrystallizedfrom ethyl acetate to giveN-(4-isopropylphenyl)-N-[(4-methylsulfonylphenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.61 g). melting point: 131-132° C.

Example 36

By the reaction and treatment in the same manner as in Example 1 using6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.05 g) asstarting materials,6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g) was obtained. melting point: 107-109° C.

Example 37

To a solution of6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) in methanol (8.6 mL) were added 10% palladium-carbon (0.09 g)and ammonium formate (0.44 g), and the mixture was stirred at roomtemperature for 24 hr. The reaction mixture was filtrated, and thesolvent was evaporated. The obtained crude crystals were recrystallizedfrom a mixed solvent of ethyl acetate and hexane to giveN-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g). melting point: 169-171° C.

Example 38

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.45 g) and(4-butylphenyl)[(4-dimethylaminophenyl)-methyl]amine (0.6 g) as startingmaterials,N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.35 g) was obtained.

¹H-NMR (CDCl₃) δ: (0.92 (3H, t, J=7.3 Hz), 1.20-1.70 (5H, m), 1.80-2.10(3H, m), 2.58 (2H, t, J=7.3 Hz), 2.50-2.70 (1H, m), 2.75-3.00 (1H, m),2.94 (6H, s), 3.70-3.80 (1H, m), 4.72 (1H, d, J=13.9 Hz), 4.93 (1H, d,J=13.9 Hz), 6.64 (2H, d, J=8.6 Hz), 6.90-7.20 (10H, m).

Example 39

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.75 g) and[(1,3-dioxaindan-5-yl)methyl](4-methoxyphenyl)amine (0.93 g) as startingmaterials,N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.15 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.43-1.45 (1H, m), 1.86-2.01 (3H, m), 2.52-2.63 (1H,m), 2.70-2.90 (2H, m), 3.73 (3H, s), 3.79 (3H, s), 3.72 (1H, t, J=8.6hz), 4.63 (1H, d, J=14 Hz), 5.00 (1H, d, J=14 Hz), 5.93 (2H, s), 6.50(1H, d, J=2.0 Hz), 6.61-6.99 (9H, m).

Example 40

By the reaction and treatment in the same manner as in Example 1 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and[(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.88 g) as startingmaterials,N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.72 g) was obtained. melting point: 89-90° C.

Example 41

By the reaction and treatment in the same manner as in Example 12 using6-chlorochroman-4-carboxylic acid (0.66 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) asstarting materials,6-chloro-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(0.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.80-2.00 (1H, m), 2.10-2.20(1H, m), 2.80-3.00 (1H, m), 2.94 (6H, s), 3.65-3.75 (1H, m), 3.90-4.05(1H, m), 4.40-4.50 (1H, m), 4.73 (1H, d, J=13.8 Hz), 4.88 (1H, d, J=13.8Hz), 6.60-7.30 (11H, m).

Example 42

By the reaction and treatment in the same manner as in Example 12 using6-bromochroman-4-carboxylic acid (0.54 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) asstarting materials,6-bromo-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(0.52 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.81-1.95 (1H, m), 2.07-2.23(1H, m), 2.81-2.98 (1H, m), 2.93 (6H, s), 3.71 (1H, t, J=6.2 Hz),3.91-4.03 (1H, m), 4.38-4.50 (1H, m), 4.71 (1H, d, J=13.9 Hz), 4.89 (1H,d, J=13.9 Hz), 6.60-6.72 (3H, m), 6.91-7.25 (8H, m).

Example 43

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and(4-isopropylphenyl)[(6-isopropylpyridin-3-yl)methyl]amine (0.46 g) asstarting materials,N-(4-isopropylphenyl)-N-[(6-isopropylpyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 1.37 (6H, d, J=6.9 Hz),1.28-1.45 (1H, m), 1.78-1.97 (3H, m), 2.47-2.71 (2H, m), 2.92 (1H, sept,J=6.9 Hz), 3.50 (1H, sept, J=6.9 Hz), 3.70 (3H, s), 3.61-3.75 (1H, m),5.02 (1H, d, J=13.9 Hz), 5.13 (1H, d, J=13.9 Hz), 6.46 (1H, d, J=2.4Hz), 6.71 (1H, dd, J=2.4, 8.4 Hz), 6.96 (1H, d, J=8.4 Hz), 7.28-7.41(4H, m), 8.01 (1H, dd, J=3.6, 8.1 Hz), 8.40 (1H, dd, J=1.8, 8.4 Hz),8.61 (1H, d, J=1.5 Hz).

Example 44

By the reaction and treatment in the same manner as in Example 12 using8-methoxychroman-4-carboxylic acid, (0.64 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methoxychroman-4-carboxamide(0.69 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.90-2.00 (1H, m), 2.15-2.30(1H, m), 2.80-3.00 (1H, m), 2.94 (6H, s), 3.77 (1H, t, J=6.3 Hz), 3.84(3H, s), 4.00-4.20 (1H, m), 4.50-4.65 (1H, m), 4.71 (1H, d, J=13.9 Hz),4.91 (1H, d, J=13.9 Hz), 6.55-7.25 (11H, m).

Example 45

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and[(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.97 g) as startingmaterials,N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.33 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.47-1.52 (1H, m), 1.86-2.03 (3H, m), 3.78 (3H, s),3.80 (3H, s), 4.76 (1H, d, J=13.9 Hz), 4.94 (1H, d, J=13.9 Hz),6.80-7.16 (12H, m)

Example 46

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.50 g) and(4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g) asstarting materials,N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidewas obtained. This was dissolved in ether, and 4N-hydrochloricacid/dioxane was added. The precipitated solid was collected byfiltration to giveN-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidemonohydrochloride (0.47 g).

melting point: 114-117° C.

Example 47

By the reaction and treatment in the same manner as in Example 12 using4-methoxyindan-1-carboxylic acid (0.20 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.27 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-carboxamide(0.24 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 2.08-2.09 (1H, m), 2.31-2.38(1H, m), 2.63-2.72 (1H, m), 2.86-2.92 (1H, m), 2.94 (6H, s), 3.79 (3H,s), 3.94-4.00 (1H, m), 4.71 (1H, d, J=13.9 Hz), 4.93 (1H, d, J=13.9 Hz),6.63-6.68 (3H, m), 6.75 (1H, d, J=7.5 Hz), 6.95-6.98 (3H, m), 7.01-7.18(4H, m).

Example 48

By the reaction and treatment in the same manner as in Example 12 using5-methoxyindan-1-carboxylic acid (0.50 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.80 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-carboxamide(1.00 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9), 2.08-2.09 (1H, m), 2.31-2.38 (1H,m), 2.63-2.77 (1H, m), 2.86-2.93 (1H, m), 2.93 (6H, s), 3.76 (3H, s),3.90 (1H, t, J=8.6 hz), 4.71 (1H, d, J=13.9 Hz), 4.92 (1H, d, J=13.9Hz), 6.63-6.73 (4H, m), 6.95-7.02 (3H, m), 7.01 (2H, d, J=8.7 Hz), 7.17(2H, d, J=8.3 Hz).

Example 49

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and[(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (2.22 g) asstarting materials,N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.64 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 1.37-1.53 (1H, m), 1.77-2.07(3H, m), 2.52-2.66 (1H, m), 2.69-2.83 (1H, m), 2.91 (1H, sept, J=6.9Hz), 3.60-3.73 (1H, m), 3.65 (3H, s), 4.58 (1H, d, J=13.9 Hz), 4.85 (1H,d, J=13.9 Hz), 5.24 (2H, s), 6.45 (1H, d, J=2.4 Hz), 6.67 (1H, dd,J=2.4, 8.4 Hz), 6.95 (1H, d, J=8.4 Hz), 7.03 (2H, d, J=8.4 Hz),7.13-7.45 (9H, m).

Example 50

By the reaction and treatment in the same manner as in Example 4 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and(4-isopropylphenyl)[(4-methoxyphenyl)methyl]amine (0.38 g) as startingmaterials,N-(4-isopropylphenyl)-N-[(4-methoxyphenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.37 g) was obtained. melting point: 83-85° C.

Example 51

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.58 g) and[(6-ethylpyridin-3-yl)methyl](4-isopropylphenyl)amine (0.71 g) asstarting materials,N-[(6-ethylpyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.28 (3H, t, J=7.7 Hz),1.40-1.57 (1H, m), 1.70-2.05 (3H, m), 2.50-2.64 (1H, m), 2.71-2.95 (4H,m), 3.70 (3H, s), 3.64-3.79 (1H, m), 4.80 (1H, d, J=13.9 Hz), 4.96 (1H,d, J=13.9 Hz), 6.47 (1H, d, J=2.4 Hz), 6.67 (1H, dd, J=2.4, 8.4 Hz),6.96 (1H, d, J=8.4 Hz), 7.00 (2H, d, J=8.4 Hz), 7.12 (1H, d, J=8.4 Hz),7.21 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=2.4, 8.4 Hz), 8.29 (1H, d, J=2.4Hz).

Example 52

By the reaction and treatment in the same manner as in Example 12 using4-benzyloxyindan-1-carboxylic acid (0.7 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) asstarting materials,4-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide(1.5 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 2.00-2.20 (1H, m), 2.30-2.45(1H, m), 2.65-2.80 (1H, m), 2.85-3.00 (1H, m), 2.94 (6H, s), 3.05-3.20(1H, m), 3.95-4.05 (1H, m), 4.72 (1H, d, J=13.8 Hz), 4.94 (1H, d, J=13.8Hz), 5.06 (2H, s), 6.60-6.80 (4H, m), 6.90-7.45 (12H, m).

Example 53

By the reaction and treatment in the same manner as in Example 37 using4-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide(1.19 g) as a starting material,N-[(4-dimethylaminophenyl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-carboxamide(0.57 g) was obtained. melting point: 158-160° C.

Example 54

To a solution ofN-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.79 g) in toluene (10 mL) was added Lawesson's reagent (0.9 g), andthe mixture was heated under reflux for 5 hr. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was purified by silica gelcolumn chromatography to giveN-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carbothioamide(0.19 g). melting point: 123-125° C.

Example 55

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and[(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.24 g)as starting materials,N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidewas obtained. This was dissolved in ether, and 4 mol/L-hydrochloricacid/dioxane (0.30 mL) was added. The solvent was evaporated. Theobtained crude crystals were recrystallized from ethyl acetate-hexane togiveN-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride ½ hydrate (0.43 g). melting point: 158-160° C.

Example 56

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and(4-isopropylphenyl)[(5-methoxypyridin-2-yl)methyl]amine (0.38 g) asstarting materials,N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidewas obtained. This is dissolved in ether, and 4 mol/L-hydrochloricacid/dioxane (0.40 mL) was added. The solvent was evaporated, and etherwas added to the residue. The precipitated crystals were collected byfiltration to giveN-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride ½ hydrate (0.54 g). melting point: 108-110° C.

Example 57

By the reaction and treatment in the same manner as in Example 4 using6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.45 g) was obtained. melting point: 111-113° C.

Example 58

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and[(2-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.40 g)as starting materials,N-[(2-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.17 (6H, d, J=6.9 Hz), 1.31-1.48 (1H, m), 1.70-2.05(3H, m), 2.48-2.68 (2H, m), 2.89 (1H, sept, J=6.9 Hz), 3.04 (6H, s),3.60-3.76 (4H, m), 4.93 (1H, d, J=13.9 Hz), 5.12 (1H, d, J=13.9 Hz),6.49 (1H, d, J=2.4 Hz), 6.72 (1H, dd, J=2.4, 8.4 Hz), 6.97 (1H, d, J=8.4Hz), 7.14 (1H, dd, J=6.0, 7.3 Hz), 7.32 (2H, d, J=8.4 Hz), 7.38 (2H, d,J=8.4 Hz), 7.95 (1H, d, J=7.4 Hz), 8.07 (1H, dd, J=1.3, 5.8 Hz).

Example 59

By the reaction and treatment in the same manner as in Example 12 using5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and[(1-ethylpyrazol-4-yl)methyl] (4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.37-1.52 (1H, m), 1.45 (3H,t, J=7.3 Hz), 1.67-2.05 (3H, m), 2.57-2.71 (2H, m), 2.92 (1H, sept,J=6.9 Hz), 3.70 (1H, t, J=6.2 Hz), 3.77 (3H, s), 4.11 (2H, q, J=7.3 Hz),4.58 (1H, d, J=13.9 Hz), 4.84 (1H, d, J=13.9 Hz), 6.54 (1H, d, J=7.7Hz), 6.65 (1H, d, J=7.7 Hz), 6.98-7.10 (3H, m), 7.22 (2H, d, J=8.4 Hz),7.33 (1H, s), 7.41 (1H, s).

Example 60

By the reaction and treatment in the same manner as in Example 12 using6-methoxyindan-1-carboxylic acid (0.29 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide(0.35 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),2.03-2.15 (1H, m), 2.26-2.39 (1H, m), 2.61-2.73 (1H, m), 2.87-3.03 (2H,m), 3.74 (3H, s), 3.93 (1H, t, J=8.1 Hz), 4.12 (2H, q, J=7.3 Hz), 4.66(1H, d, J=13.9 Hz), 4.79 (1H, d, J=13.9 Hz), 6.68 (1H, d, J=2.4 Hz),6.69 (1H, dd, J=2.4, 8.4 Hz), 7.00-7.10 (3H, m), 7.23 (2H, d, J=8.4 Hz),7.32 (1H, s), 7.40 (1H, s).

Example 61

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) asstarting materials,5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.72 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.39-1.55 (1H, m), 1.45 (3H,t, J=7.3 Hz), 1.78-2.09 (3H, m), 2.68-2.80 (2H, m), 2.92 (1H, sept,J=6.9 Hz), 3.72 (1H, t, J=6.2 Hz), 4.13 (2H, q, J=7.3 Hz), 4.58 (1H, d,J=13.9 Hz), 4.84 (1H, d, J=13.9 Hz), 5.03 (2H, s), 6.56 (1H, d, J=7.7Hz), 6.70 (1H, d, J=7.7 Hz), 6.98-7.12 (3H, m), 7.20-7.42 (9H, m).

By the reaction and treatment in the same manner as in Example 37 using5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.72 g),N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained. melting point: 212-215° C.

Example 62

By the reaction and treatment in the same manner as in Example 6 usingN-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.49 g) and 1-methanesulfonyloxy-2-(4-methoxyphenyl)ethane (0.38 g) asstarting materials,N-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.15 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.78-2.09(3H, m), 2.51-2.63 (1H, m), 2.69-2.97 (4H, m), 3.65-4.15 (9H, m), 6.51(1H, d, J=2.4 Hz), 6.67 (1H, dd, J=2.4, 8.4 Hz), 6.75-6.88 (2H, m), 6.96(1H, d, J=8.4 Hz), 7.06-7.29 (6H, m).

Example 63

By the reaction and treatment in the same manner as in Example 6 usingN-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.49 g) and 1-methanesulfonyloxy-3-(4-methoxyphenyl)propane (0.40 g) asstarting materials,N-(4-isopropylphenyl)-N-[3-(4-methoxyphenyl)propyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.40-1.53 (1H, m), 1.81-2.09(5H, m), 2.51-2.64 (3H, m), 2.70-2.85 (1H, m), 2.93 (1H, sept, J=6.9Hz), 3.68-3.87 (9H, m), 6.57 (1H, d, J=2.4 Hz), 6.67 (1H, dd, J=2.4, 8.4Hz), 6.80 (2H, d, J=8.4 Hz), 6.95 (1H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4Hz), 7.14-7.33 (4H, m).

Example 64

By the reaction and treatment in the same manner as in Example 6 usingN-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.49 g) and 1-methanesulfonyloxy-4-(4-methoxyphenyl)butane (0.43 g) asstarting materials,N-(4-isopropylphenyl)-N-[4-(4-methoxyphenyl)butyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.25 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.40-1.68 (5H, m), 1.80-2.05(3H, m), 2.50-2.62 (3H, m), 2.71-2.83 (1H, m), 2.93 (1H, sept, J=6.9Hz), 3.64-3.88 (9H, m), 6.56 (1H, d, J=2.4 Hz), 6.67 (1H, dd, J=2.4, 8.4Hz), 6.80 (2H, d, J=8.4 Hz), 6.95 (1H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4Hz), 7.13 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz).

Example 65

By the reaction and treatment in the same manner as in Example 4 using7-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) asstarting materials,7-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.61 g) was obtained. melting point: 100-101° C.

Example 66

By the reaction and treatment in the same manner as in Example 4 using4-benzyloxyindan-1-carboxylic acid (0.54 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) asstarting materials,4-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide(0.79 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),2.04-2.18 (1H, m), 2.24-2.39 (1H, m), 2.65-2.80 (1H, m), 2.92 (1H, sept,J=6.9 Hz), 3.06-3.20 (1H, m), 3.98 (1H, t, J=6.2 Hz), 4.12 (2H, q, J=7.3Hz), 4.65 (1H, d, J=13.9 Hz), 4.79 (1H, d, J=13.9 Hz), 5.06 (2H, s),6.67 (1H, d, J=7.7 Hz), 6.70 (1H, d, J=7.7 Hz), 7.00-7.10 (3H, m),7.20-7.43 (9H, m).

Example 67

By the reaction and treatment in the same manner as in Example 4 usingindan-1-carboxylic acid (0.24 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide(0.23 g) was obtained. melting point: 83-84° C.

Example 68

By the reaction and treatment in the same manner as in Example 4 using6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) asstarting materials,6-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.65 g) was obtained. melting point: 122-124° C.

Example 69

By the reaction and treatment in the same manner as in Example 12 using6-fluorochroman-4-carboxylic acid (0.29 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-carboxamide(0.42 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 1.46 (3H, t, J=7.3 Hz),1.84-1.97 (1H, m), 2.08.2.20 (1H, m), 2.94 (1H, sept, J=6.9 Hz), 3.72(1H, t, J=6.2 Hz), 3.89-4.00 (1H, m), 4.12 (2H, q, J=7.3 Hz), 4.35-4.45(1H, m), 4.62 (1H, d, J=13.9 Hz), 4.79 (1H, d, J=13.9 Hz), 6.55 (1H, dd,J=2.4, 8.4 Hz), 6.69-6.83 (2H, m), 7.04 (2H, d, J=8.4 Hz), 7.21-7.31(3H, s), 7.40 (1H, s).

Example 70

By the reaction and treatment in the same manner as in Example 12 using6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.29 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxamide(0.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.47 (3H, t, J=7.3 Hz),1.60-1.74 (4H, m), 1.79-1.91 (1H, m), 1.92-2.02 (1H, m), 2.12-2.24 (1H,m), 2.48-2.60 (1H, m), 2.85 (1H, sept, J=6.9 Hz), 3.66 (1H, dd, J=1.5,9.6 Hz), 4.14 (2H, q, J=7.3 Hz), 4.63 (1H, d, J=13.9 Hz), 4.83 (1H, d,J=13.9 Hz), 6.61-6.77 (2H, m), 6.93-7.13 (6H, m), 7.32 (1H, s), 7.45(1H, s).

Example 71

By the reaction and treatment in the same manner as in Example 12 usingchroman-4-carboxylic acid (0.27 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(0.52 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),1.86-1.98 (1H, m), 2.10-2.22 (1H, m), 2.94 (1H, sept, J=6.9 Hz), 3.76(1H, t, J=6.2 Hz), 3.92-4.03 (1H, m), 4.13 (2H, q, J=7.3 Hz), 4.39-4.49(1H, m), 4.62 (1H, d, J=13.9 Hz), 4.80 (1H, d, J=13.9 Hz), 6.74-6.89(3H, m), 7.00-7.12 (3H, m), 7.25 (2H, d, J=8.4 Hz), 7.32 (1H, s), 7.38(1H, s).

Example 72

By the reaction and treatment in the same manner as in Example 12 using6-methoxychroman-4-carboxylic acid (0.31 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide(0.39 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),1.85-1.97 (1H, m), 2.12.2.24 (1H, m), 2.94 (1H, sept, J=6.9 Hz), 3.67(3H, s), 3.74 (1H, t, J=6.2 Hz), 3.87-3.99 (1H, m), 4.12 (2H, q, J=7.3Hz), 4.33-4.45 (1H, m), 4.57 (1H, d, J=13.9 Hz), 4.85 (1H, d, J=13.9Hz), 6.40 (1H, d, J=2.4 Hz), 6.62-6.76 (2H, m), 7.06 (2H, d, J=8.4 Hz),7.25 (2H, d, J=8.4 Hz), 7.32 (1H, s), 7.41 (1H, s).

Example 73

By the reaction and treatment in the same manner as in Example 12 using7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.33 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.46 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.17 (6H, dd, J=2.6, 6.9 Hz), 1.25 (6H, d, J=6.9 Hz),1.41-1.57 (1H, m), 1.46 (3H, t, J=7.3 Hz), 1.82-2.07 (3H, m), 2.68-2.80(2H, m), 2.92 (1H, sept, J=6.9 Hz), 3.71 (1H, t, J=6.2 Hz), 4.12 (2H, q,J=7.3 Hz), 4.43 (1H, d, J=13.9 Hz), 5.01 (1H, d, J=13.9 Hz), 6.74 (1H,s), 6.95 (1H, d, J=(0.8 Hz), 7.07 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4Hz), 7.36 (1H, s), 7.46 (1H, s).

Example 74

By the reaction and treatment in the same manner as in Example 4 using7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.29 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) was obtained. melting point: 110-112° C.

Example 75

By the reaction and treatment in the same manner as in Example 37 using7-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.48 g),N-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.34 g) was obtained. melting point: 169-170° C.

Example 76

By the reaction and treatment in the same manner as in Example 37 using4-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide(0.70 g),N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-carboxamide(0.51 g) was obtained. melting point: 205-206° C.

Example 77

By the reaction and treatment in the same manner as in Example 37 using6-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.56 g),N-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) was obtained. melting point: 146-147° C.

Example 78

By the reaction and treatment in the same manner as in Example 4 using5-methoxyindan-1-carboxylic acid (0.29 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-carboxamide(0.47 g) was obtained. melting point: 115-116° C.

Example 79

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.26 g) and[(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.46 g) asstarting materials,N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.55 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.39-1.55 (1H, m), 1.82-2.02(3H, m), 2.58-2.70 (1H, m), 2.78-2.98 (2H, m), 3.71 (1H, t, J=6.2 Hz),4.61 (1H, d, J=13.9 Hz), 4.83 (1H, d, J=13.9 Hz), 5.26 (2H, s), 6.88(1H, d, J=8.4 Hz), 6.98-7.13 (5H, m), 7.16-7.24 (4H, m), 7.28-7.43 (2H,m).

Example 80

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and[(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.61 g) asstarting materials,5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.38-1.53 (1H, m), 1.77-2.07(3H, m), 2.67-2.77 (2H, m), 2.91 (1H, sept, J=6.9 Hz), 3.70 (1H, t,J=6.2 Hz), 4.58 (1H, d, J=13.9 Hz), 4.84 (1H, d, J=13.9 Hz), 5.02 (2H,s), 5.26 (2H, s), 6.54 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=7.7 Hz),6.93-7.07 (3H, m), 7.13-7.47 (14H, m).

By the reaction and treatment in the same manner as in Example 37 using5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g),N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.47 g) was obtained. melting point: 130.1° C.

Example 81

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and(4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.35 g) asstarting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.57 (1H, m), 1.78-2.10(3H, m), 2.70-2.80 (1H, m), 2.90 (1H, sept, J=6.9 Hz), 3.74 (1H, t,J=6.2 Hz), 3.93 (3H, s), 4.79 (1H, d, J=13.9 Hz), 4.89 (1H, d, J=13.9Hz), 5.03 (2H, s), 6.62 (1H, d, J=7.5 Hz), 6.67-6.75 (2H, m), 6.97-7.12(3H, m), 7.17-7.47 (7H, m), 7.63 (1H, dd, J=2.4, 8.4 Hz), 7.89 (1H, d,J=2.4 Hz).

By the reaction and treatment in the same manner as in Example 37 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g),5-hydroxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.25 g) was obtained. melting point: 157.9° C.

Example 82

1-(tert-Butyloxycarbonyl)-4-(hydroxymethyl)pyrazole-(3.98 g) wasdissolved in methylene chloride (50 mL), and methanesulfonyl chloride(1.63 mL) was added under ice-cooling. The mixture was stirred at roomtemperature for one day. The reaction mixture was concentrated andpartitioned between water and chloroform. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give a residue (4.20 g). A white amorphoussolid (5.20 g) obtained by the reaction and treatment in the same manneras in Example 6 using the residue andN-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(5.96 g) was dissolved in 4 mol/L-HCl/dioxane (50 mL). The mixture wasstirred at room temperature for 3 hr, and the reaction mixture wasconcentrated under reduced pressure. Ethyl acetate and hexane were addedto the residue. The precipitated solid was collected by filtration togiveN-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-N-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (4.17 g).

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 1.25-1.42 (1H, m), 1.78-1.98(3H, m), 2.46-2.71 (2H, m), 2.91 (1H, sept, J=6.9 Hz), 3.60 (1H, t,J=6.2 Hz), 3.66 (3H, s), 4.70 (1H, d, J=13.9 Hz), 4.81 (1H, d, J=13.9Hz), 5.24 (2H, s), 6.42 (1H, d, J=2.4 Hz), 6.69 (1H, dd, J=2.4, 8.4 Hz),6.95 (1H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz),7.83 (2H, s).

Example 83

N-(4-Isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) and cyclopentyl bromide (0.12 mL) were dissolved in DMF (5 mL),and sodium hydride (0.09 g) was added under ice-cooling. The mixture wasstirred at the same temperature for 30 min and then at room temperaturefor 5 hr. The reaction mixture was concentrated under reduced pressureand partitioned between water and ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography to giveN-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.38 g).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.62-2.20(11H, m), 2.52-2.65 (1H, m), 2.70-2.84 (1H, m), 2.89 (1H, sept, J=6.9Hz), 3.66 (3H, s), 3.70 (1H, t, J=6.2 Hz), 4.50 (1H, d, J=13.9 Hz), 4.60(1H, quint, J=6.9 Hz), 4.92 (1H, d, J=13.9 Hz), 6.43 (1H, d, J=2.4 Hz),6.66 (1H, dd, J=2.4, 8.4 Hz), 6.94 (1H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4Hz), 7.22 (2H, d, J=8.4 Hz), 7.34 (2H, s), 7.44 (2H, s).

Example 84

By the reaction and treatment in the same manner as in Example 83 usingN-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) and isopropyl iodide (0.11 mL) as starting materials,N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.26 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.36-1.53 (1H, m), 1.47 (6H,d, J=6.9 Hz), 1.79-2.06 (3H, m), 2.52-2.65 (1H, m), 2.70-2.84 (1H, m),2.92 (1H, sept, J=6.9 Hz), 3.68 (3H, s), 3.70 (1H, t, J=6.2 Hz), 4.44(1H, quint, J=6.9 Hz), 4.50 (1H, d, J=13.9 Hz), 4.94 (1H, d, J=13.9 Hz),6.43 (1H, d, J=2.4 Hz), 6.66 (1H, dd, J=2.4, 8.4 Hz), 6.94 (1H, d, J=8.4Hz), 7.05 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.35 (2H, s), 7.44(2H, s).

Example 85

By the reaction and treatment in the same manner as in Example 83 usingN-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) and ethyl iodide (0.09 mL) as starting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained. This was dissolved in ethyl acetate, and oxalicacid (0.07 g) was added. The precipitated solid was collected byfiltration to giveN-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamideoxalate (0.06 g).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.36-1.53 (1H, m), 1.32 (3H,t, J=6.9 Hz), 1.77-1.98 (3H, m), 2.47-2.70 (2H, m), 2.90 (1H, sept,J=6.9 Hz), 3.59 (1H, t, J=6.2 Hz), 3.64 (3H, s), 4.07 (2H, q, J=6.9 Hz),4.56 (1H, d, J=13.9 Hz), 4.80 (1H, d, J=13.9 Hz), 6.41 (1H, d, J=2.4Hz), 6.69 (1H, dd, J=2.4, 8.4 Hz), 6.94 (1H, d, J=8.4 Hz), 7.19 (2H, d,J=8.4 Hz), 7.27 (1H, s), 7.33 (2H, d, J=8.4 Hz), 7.53 (1H, s).

Example 86

By the reaction and treatment in the same manner as in Example 83 usingN-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) and propyl iodide (0.01 mL) as starting materials,N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=6.9 Hz), 1.24 (6H, d, J=6.9 Hz),1.38-1.54 (1H, m), 1.77-2.04 (5H, m), 2.52-2.64 (1H, m), 2.70-2.84 (1H,m), 2.92 (1H, sept, J=6.9 Hz), 3.65-3.75 (1H, m), 3.68 (3H, s), 4.02(2H, t, J=6.9 Hz), 4.07 (2H, q, J=6.9 Hz), 4.55 (1H, d, J=13.9 Hz), 4.88(1H, d, J=13.9 Hz), 6.44 (1H, d, J=2.4 Hz), 6.66 (1H, dd, J=2.4, 8.4Hz), 6.95 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4Hz), 7.35 (1H, s), 7.40 (1H, s).

Example 87

By the reaction and treatment in the same manner as in Example 82 using1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (578 mg) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.17 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (790 mg) was obtained. melting point: 184.7° C.

Example 88

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.79 g) and ethyl iodide (0.12 mL) as starting materials,5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),1.40-1.57 (1H, m), 1.75-2.07 (3H, m), 2.65-2.77 (2H, m), 2.72 (1H, sept,J=6.9 Hz), 3.64 (1H, t, J=6.2 Hz), 4.14 (2H, q, J=7.3 Hz), 4.61 (1H, d,J=13.9 Hz), 4.85 (1H, d, J=13.9 Hz), 5.03 (2H, s), 6.53 (1H, d, J=7.7Hz), 6.72 (1H, d, J=7.7 Hz), 7.03 (1H, t, J=7.7 Hz), 7.24-7.43 (8H, m),8.39 (1H, d, J=1.5 Hz).

Example 89

By the reaction and treatment in the same manner as in Example 37 using5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g),N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained. melting point: 172.8° C.

Example 90

To a solution ofN-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(29.9 g) in ethanol (300 mL) was added 4 mol/L-HCl/dioxane (17.5 mL) at0° C. The precipitated white solid was collected by filtration andrecrystallized from ethanol:water (2:3) to giveN-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride ½ hydrate (24.1 g). melting point: 146.9° C.

Example 91

(R)-7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.65 g)and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.0 g) werereacted and treated in the same manner as in Example 12. The obtainedsolid was dissolved in ethyl acetate. Thereto was added 4mol/L-HCl/ethyl acetate (1 mL). The solvent was evaporated under reducedpressure. The precipitated solid was recrystallized twice from ethanolto give(R)—N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride ½ ethanol (0.20 g).

melting point: 151-159° C.

optical purity 99.8% e.e.

Analysis Conditions

column: CHIRALCEL OD (DAICEL)

developing solvent: hexane/isopropanol=85/15

flow rate: 0.5 mL/min

UV detection: 254 nm

retention time: 26 min

[α]_(D)+113.5° (24° C., methanol, c=1.0)

Example 92

By the reaction and treatment in the same manner as in Example 91 using(S)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.95 g)and [(4-dimethylaminophenyl)methyl] (4-isopropylphenyl)amine (1.48 g) asstarting materials, (S)—N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride ½ ethanol (1.09 g) was obtained. melting point: 154-159°C.

optical purity 99.5% e.e.

Analysis Conditions

column: CHIRALCEL OD (DAICEL)

developing solvent: hexane/isopropanol=85/15

flow rate: 0.5 mL/min

UV detection: 254 nm

retention time: 21.5 min

[α]_(D)=−113.1° (20° C., methanol, c=1.0)

Example 93

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g) and(4-acetylphenyl)[(4-methoxyphenyl)methyl]amine (0.78 g) as startingmaterials,N-(4-acetylphenyl)-7-methoxy-N-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.39-1.57 (1H, m), 1.81-2.08 (3H, m), 2.59 (3H, s),2.70-2.85 (1H, m), 3.60-3.70 (1H, m), 3.72 (3H, s), 3.79 (3H, s), 4.75(1H, d, J=13.9 Hz), 5.07 (1H, d, J=13.9 Hz), 6.50 (1H, d, J=2.4 Hz),6.69 (1H, dd, J=2.4, 8.4 Hz), 6.76-6.86 (2H, m), 6.97 (2H, d, J=8.4 Hz),7.10-7.22 (4H, m), 7.90-7.98 (2H, m).

Example 94

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and{[4-(diethoxymethyl)phenyl]-methyl}(4-isopropylphenyl)amine (0.65 g) asstarting materials. The obtained residue was dissolved in a mixedsolvent (15 mL) of methanol:1 mol/L-hydrochloric acid (1:2) and heatedunder reflux for 3 hr. The reaction mixture was concentrated underreduced pressure and partitioned between water and ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to giveN-[(4-formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.58 (1H, m), 1.85-2.10(3H, m), 2.50-2.63 (1H, m), 2.70-2.85 (1H, m), 2.89 (1H, sept, J=6.9Hz), 3.71 (3H, s), 3.75-3.84 (1H, m), 4.89 (1H, d, J=13.9 Hz), 5.10 (1H,d, J=13.9 Hz), 6.53 (1H, d, J=2.4 Hz), 6.68 (1H, dd, J=2.4, 8.4 Hz),6.96 (1H, d, J=8.4 Hz), 7.02 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz),7.45 (2H, d, J=8.4 Hz), 7.81 (2H, d, J=8.4 Hz), 9.98 (1H, s).

Example 95

N-[(4-Formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) was dissolved in a mixed solvent (10 mL) of ethanol:tetrahydrofuran (2:1), and sodium borohydride (0.15 g) was added underice-cooling. The mixture was stirred at room temperature for 3 hr. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography to giveN-{[4-(hydroxymethyl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.25 g). melting point: 143.2° C.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.58 (1H, m), 1.82-2.10(3H, m), 2.51-2.65 (1H, m), 2.72-2.87 (1H, m), 2.89 (1H, sept, J=6.9Hz), 3.71 (3H, s), 3.68-3.79 (1H, m), 4.68 (2H, s), 4.75 (1H, d, J=13.9Hz), 5.08 (1H, d, J=13.9 Hz), 6.52 (1H, d, J=2.4 Hz), 6.68 (1H, dd,J=2.4, 8.4 Hz), 6.92-7.06 (3H, m), 7.18 (2H, d, J=8.4 Hz), 7.26-7.37(4H, m).

Example 96

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g) and[(4-bromophenyl)methyl](4-octylphenyl)amine (1.12 g) as startingmaterials,N-[(4-bromophenyl)methyl]-7-methoxy-N-(4-octylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.15 g) was obtained.

¹H-NMR (CDCl₃) δ: (0.87 (3H, t, J=4.5 Hz), 1.20-1.38 (12H, m), 1.42-1.58(1H, m), 1.82-2.08 (3H, m), 2.52-2.65 (3H, m), 2.71-2.85 (1H, m), 3.70(3H, s), 3.67-3.81 (1H, m), 4.72 (1H, d, J=14.1 Hz), 5.00 (1H, d, J=14.0Hz), 6.48 (1H, d, J=2.5 Hz), 6.68 (1H, dd, J=2.6, 8.4 Hz), 6.91-7.01(3H, m), 7.10-7.18 (4H, m), 7.37-7.45 (2H, m).

Example 97

By the reaction and treatment in the same manner as in Example 12 using8-(benzyloxy)chroman-4-carboxylic acid (0.47 g) and(4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine 0.43 g) asstarting materials,8-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroman-4-carboxamide(0.61 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.88-2.02 (1H, m), 2.11-2.24(1H, m), 2.91 (1H, sept, J=6.9 Hz), 3.79 (1H, t, J=6.3 Hz), 3.92 (3H,s), 4.05-4.16 (1H, m), 4.51-4.61 (1H, m), 4.78 (1H, d, J=13.9 Hz), 4.87(1H, d, J=13.9 Hz), 5.12 (2H, s), 6.48-6.57 (1H, m), 6.65-6.75 (3H, m),6.98 (2H, d, J=8.4 Hz), 7.19-7.43 (7H, m), 7.60 (1H, dd, J=2.4, 8.4 Hz),7.88 (1H, d, J=2.4 Hz).

Example 98

By the reaction and treatment in the same manner as in Example 17 using8-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroman-4-carboxamide(0.58 g) as a starting material,8-hydroxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroman-4-carboxamide(0.35 g) was obtained.

melting point: 141.2° C.

Example 99

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42 g) and[(2,6-dimethoxypyridin-3-yl)methyl](4-isopropylphenyl)amine (0.43 g) asstarting materials,5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.71 g) was obtained.

By the reaction and treatment in the same manner as in Example 17 usingthis compound (0.70 g),N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) was obtained. melting point: 190.5° C.

Example 100

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42 g) and(4-isopropylphenyl)[(6-phenoxypyridin-3-yl)methyl]amine (0.47 g) asstarting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.38-1.55 (1H, m), 1.77-2.09(3H, m), 2.67-2.87 (2H, m), 2.88 (1H, sept, J=6.9 Hz), 3.70-3.80 (1H,m), 4.82 (1H, d, J=14.2 Hz), 4.90 (1H, d, J=14.2 Hz), 5.01 (2H, s), 6.62(1H, d, J=7.7 Hz), 6.74 (1H, d, J=8.5 Hz), 6.85 (1H, d, J=8.5 Hz),6.97-7.42 (15H, m), 7.71-7.79 (1H, m), 7.94 (1H, d, J=2.3 Hz).

Example 101

To a solution of5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) in methanol (3 mL) were added 10% palladium carbon (0.05 g) andammonium formate (0.23 g), and the mixture was stirred at roomtemperature for one day. The reaction mixture was filtrated, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide.This compound was dissolved in ethyl acetate, and 4 mol/L-hydrochloricacid/dioxane (0.20 mL) was added. The precipitated solid was collectedby filtration to give5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.11 g).

¹H-NMR (DMSO-d₆) δ: 1.19 (6H, d, J=6.9 Hz), 1.27-1.43 (1H, m), 1.73-2.00(3H, m), 2.67-2.87 (2H, m), 2.89 (1H, sept, J=6.9 Hz), 3.51-3.71 (1H,m), 4.79 (1H, d, J=14.7 Hz), 4.92 (1H, d, J=14.7 Hz), 6.46 (1H, d, J=7.5Hz), 6.62 (1H, d, J=7.8 Hz), 6.84-6.92 (1H, m), 7.00 (1H, d, J=8.4 Hz),7.07-7.47 (9H, m), 7.70 (1H, dd, J=2.4, 8.4 Hz), 7.91 (1H, d, J=2.1 Hz).

Example 102

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and[(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.54 g)as starting materials,5-benzyloxy-N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.38-1.53 (1H, m), 1.77-2.10(3H, m), 2.61-2.78 (2H, m), 2.89 (1H, sept, J=6.9 Hz), 3.08 (6H, s),3.67-3.77 (1H, m), 4.71 (1H, d, J=14.1 Hz), 4.85 (1H, d, J=14.1 Hz),5.03 (2H, s), 6.48 (1H, d, J=8.7 Hz), 6.64 (1H, d, J=7.8 Hz), 6.71 (1H,d, J=8.1 Hz), 6.95-7.09 (3H, m), 7.19 (2H, d, J=8.4 Hz), 7.23-7.44 (5H,m), 7.54 (1H, dd, J=2.4, 8.7 Hz), 7.86 (1H, d, J=2.1 Hz).

Example 103

By the reaction and treatment in the same manner as in Example 17 using5-benzyloxy-N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) as a starting material,N-[(6-dimethylaminopyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained. melting point: 186.6° C.

Example 104

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.85 g) and(4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.87 g) asstarting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.21 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.41-1.57 (1H, m), 1.80-2.10(3H, m), 2.65-2.84 (2H, m), 2.93 (1H, sept, J=6.9 Hz), 3.71-3.82 (1H,m), 4.70 (1H, d, J=14.4 Hz), 4.92 (1H, d, J=14.4 Hz), 5.03 (2H, s), 6.60(1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1 Hz), 7.00-7.16 (3H, m), 7.22-7.48(10H, m), 7.58 (1H, s), 7.66 (2H, d, J=7.6 Hz), 7.95 (1H, s).

Example 105

To a solution of5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.04 g) in methanol (10 mL) were added 10% palladium carbon (0.10 g)and ammonium formate (0.59 g), and the mixture was stirred at roomtemperature for one day. The reaction mixture was filtrated, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give5-hydroxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g).

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.36-1.51 (1H, m), 1.78-2.08(3H, m), 2.50-2.71 (2H, m), 2.93 (1H, sept, J=6.9 Hz), 3.70-3.81 (1H,m), 4.72 (1H, d, J=14.4 Hz), 4.94 (1H, d, J=14.4 Hz), 6.36 (1H, d, J=7.8Hz), 6.42 (1H, d, J=7.5 Hz), 6.75 (1H, d, J=7.8 Hz), 7.12 (1H, d, J=8.4Hz), 7.21-7.33 (3H, m), 7.39-7.49 (2H, m), 7.53 (1H, brs), 7.59 (1H, s),7.69 (2H, d, J=7.5 Hz), 8.01 (1H, s).

Example 106

To a solution ofN-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) in dimethylformamide (10 mL) were added2-chloro-N,N-dimethylethylamine hydrochloride (0.26 g) and potassiumcarbonate (0.62 g), and the mixture was stirred with heating at 50° C.for 3 hr. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was evaporated, and the residue waspurified by silica gel column chromatography to give6-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide⅕ hydrate (0.1 g). melting point: 132.6° C.

MS (ESI) m/z: 514 [MH]⁺

Example 107

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) and 2-bromoethanol (0.16 mL) as starting materials,N-[(4-dimethylaminophenyl)methyl]-6-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.28 g) was obtained. melting point: 141.4° C.

Example 108

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) and 2-bromoethanol (0.32 mL) as starting materials,N-[(4-dimethylaminophenyl)methyl]-5-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.49 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.20-1.30 (6H, m), 1.35-1.50 (1H, m), 1.70-2.10 (3H,m), 2.60-2.70 (2H, m), 2.80-3.00 (1H, m), 2.94 (6H, s), 3.65-3.75 (1H,m), 3.85-4.00 (2H, m), 4.00-4.10 (2H, m), 4.72 (1H, d, J=13.8 Hz), 4.91(1H, d, J=13.8 Hz), 6.60-6.70 (4H, m), 6.90-7.20 (7H, m).

Example 109

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) and ethyl iodide (0.14 mL) as starting materials,7-ethoxy-N-{[4-(ethylmethylamino)phenyl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.1 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.12 (3H, t, J=7.2 Hz), 1.23 (6H, d, J=6.9 Hz), 1.37(3H, t, J=6.9 Hz), 1.30-1.55 (1H, m), 1.80-2.10 (3H, m), 2.50-2.65 (1H,m), 2.70-3.00 (2H, m), 2.90 (3H, s), 3.39 (2H, q, J=7.2 Hz), 3.60-3.70(1H, m), 3.75-4.00 (2H, m), 4.53 (1H, d, J=13.8 Hz), 5.08 (1H, d, J=13.8Hz), 6.45-6.70 (4H, m), 6.85-7.20 (7H, m).

Example 110

N-[(4-Dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) and ethyl iodide (0.14 mL) were dissolved in dimethylformamide(5 mL), and sodium hydride (0.07 g) was added under ice-cooling. Themixture was stirred at room temperature for 24 hr. The reaction mixturewas partitioned between water and ethyl acetate. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography to giveN-[(4-dimethylaminophenyl)methyl]-7-ethoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.27 g).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.37 (3H, t, J=7.0 Hz),1.30-1.60 (1H, m), 1.80-2.10 (3H, m), 2.50-2.65 (1H, m), 2.70-3.00 (2H,m), 2.94 (6H, s), 3.60-3.75 (1H, m), 3.75-3.95 (2H, m), 4.54 (1H, d,J=13.9 Hz), 5.09 (1H, d, J=13.9 Hz), 6.45-6.55 (1H, m), 6.60-6.70 (3H,m), 6.85-7.00 (3H, m), 7.05-7.20 (4H, m).

Example 111

By the reaction and treatment in the same manner as in Example 110 usingN-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) and butyl bromide (0.18 mL) as starting materials,7-butoxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.15 g) was obtained.

¹H-NMR (CDCl₃) δ: (0.98 (3H, t, J=7.3 Hz), 1.23 (6H, d, J=6.9 Hz)1.40-1.60 (3H, m), 1.65-2.10 (5H, m), 2.50-2.65 (1H, m), 2.70-3.00 (2H,m), 2.94 (6H, s), 3.65-3.70 (1H, m), 3.75-3.90 (2H, m), 4.54 (1H, d,J=13.9 Hz), 5.10 (1H, d, J=13.9 Hz), 6.45-6.55 (1H, m), 6.60-6.70 (3H,m), 6.85-7.00 (3H, m), 7.10-7.20 (4H, m).

Example 112

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) and 2-iodopropane (0.17 mL) as starting materials,N-[(4-dimethylaminophenyl)methyl]-7-isopropoxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(35 mg) was obtained.

¹H-NMR (CDCl₃) δ: 1.10-1.35 (12H, m), 1.35-1.55 (1H, m), 1.80-2.10 (3H,m), 2.50-2.65 (1H, m), 2.70-3.00 (2H, m), 2.94 (6H, s), 3.60-3.80 (1H,m), 4.30-4.45 (1H, m), 4.53 (1H, d, J=13.8 Hz), 5.10 (1H, d, J=13.8 Hz),6.45-6.55 (1H, m), 6.60-6.75 (3H, m), 6.85-7.05 (3H, m), 7.10-7.25 (4H,m).

Example 113

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.32 g) asstarting materials,5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.54 g) was obtained. This compound was dissolved in ethyl acetate, andoxalic acid was added. The precipitated solid was subjected torecrystallization from ethyl acetate to give5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamideoxalate ¼ hydrate (93.8 mg).

melting point: 155.7° C.

Example 114

By the reaction and treatment in the same manner as in Example 110 usingN-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g), 2-chloro-N,N-dimethylethylamine hydrochloride (0.36 g) andsodium iodide (0.51 g) as starting materials,7-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(36 mg) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.55 (1H, m), 1.70-2.05(5H, m), 2.33 (6H, s), 2.50-2.95 (3H, m), 2.94 (6H, s), 3.60-3.70 (1H,m), 3.85-4.05 (2H, m), 4.64 (1H, d, J=13.9 Hz), 4.99 (1H, d, J=13.9 Hz),6.50-6.75 (4H, m), 6.90-7.20 (7H, m).

Example 115

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) and (5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl chloride(0.38 g) as starting materials,5-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.16 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.50 (1H, m), 1.75-2.10(3H, m), 2.64 (2H, t, J=6.6 Hz), 2.85-2.95 (1H, m), 2.94 (6H, s),2.65-2.75 (1H, m), 3.84 (2H, t, J=9.3 Hz), 4.23 (2H, t, J=9.3 Hz), 4.61(2H, s), 4.72 (1H, d, J=14.1 Hz), 4.91 (1H, d, J=14.1 Hz), 5.67 (1H, s),6.60-6.75 (4H, m), 6.90-7.20 (7H, m).

Example 116

By the reaction and treatment in the same manner as in Example 106 usingN-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.32 g) asstarting materials,N-[(4-dimethylaminophenyl)-methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) was obtained. Oxalic acid was added to this compound. Byrecrystallization from isopropyl alcohol,N-[(4-dimethylaminophenyl)methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamideoxalate ⅘ hydrate (0.18 g) was obtained.

melting point: 100.8° C.

Example 117

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.3 g) andmethyl 4-{[(4-isopropylphenyl)amino]methyl}benzoate (2.3 g) as startingmaterials, methyl4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoate(2.56 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.80-2.10(3H, m), 2.70-2.76 (2H, m), 2.80-2.95 (1H, m), 3.72-3.82 (1H, m), 3.92(3H, s), 4.90 (1H, d, J=14.2 Hz), 5.04 (1H, d, J=14.2 Hz), 5.03 (2H, s),6.64 (1H, d, J=7.7 Hz), 6.73 (1H, d, J=8.1 Hz), 6.95-7.45 (12H, m), 7.97(2H, d, J=8.3 Hz).

Example 118

Methanol (14 mL) and 1 mol/L-aqueous sodium hydroxide solution (7 mL)were added to methyl4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoate(2.56 g), and the mixture was stirred with heating at 50-60° C. Afterthe completion of the reaction, the reaction mixture was neutralizedwith conc. hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography to give4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoicacid (2 g).

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.80-2.15(3H, m), 2.70-2.80 (2H, m), 2.82-2.95 (1H, m), 3.72-3.85 (1H, m), 4.94(1H, d, J=14.1 Hz), 5.06 (1H, d, J=14.1 Hz), 5.03 (2H, s), 6.66 (1H, d,J=7.8 Hz), 6.73 (1H, d, J=8.1 Hz), 6.90-7.50 (12H, m), 8.04 (2H, d,J=8.4 Hz).

Example 119

By the reaction and treatment in the same manner as in Example 17 using4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoicacid (2 g) as a starting material,4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoicacid dihydrate (0.13 g) was obtained. melting point: 231.4° C.

Example 120

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.7 g) and[(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) asstarting materials, N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.18 g) was obtained.

MS (ESI) m/z: 418 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.30 (3H, t, J=7.5 Hz),1.40-1.60 (1H, m), 1.80-2.10 (3H, m), 2.55-2.70 (1H, m), 2.82 (2H, q,J=7.5 Hz), 2.72-3.00 (2H, m), 3.65-3.80 (1H, m), 4.90 (1H, d, J=14.6Hz), 5.03 (1H, d, J=14.6 Hz), 6.56 (1H, d, J=3.4 Hz), 6.62 (1H, d, J=3.4Hz), 6.90-7.30 (8H, m).

Example 121

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13 g) and[(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) asstarting materials,5-benzyloxy-N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.01 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.29 (3H, t, J=7.5 Hz),1.35-1.55 (1H, m), 1.80-2.10 (3H, m), 2.81 (2H, q, J=7.5 Hz), 2.60-3.00(3H, m), 3.70-3.80 (1H, m), 4.90 (1H, d, J=14.4 Hz), 5.03 (1H, d, J=14.4Hz), 5.03 (2H, s), 6.50-6.75 (4H, m), 7.00-7.12 (3H, m), 7.15-7.50 (7H,m).

Example 122

By the reaction and treatment in the same manner as in Example 12 using8-benzyloxychroman-4-carboxylic acid (0.54 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.51 g) asstarting materials,8-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(1 g) was obtained.

MS (ESI) m/z: 535 [MH]⁺

By the reaction and treatment in the same manner as in Example 17 usingthis compound,N-[(4-dimethylaminophenyl)methyl]-8-hydroxy-N-(4-isopropylphenyl)chroman-4-carboxamide(0.7 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.90-2.30 (2H, m), 2.85-3.10(1H, m), 2.94 (6H, s), 3.70-3.85 (1H, m), 4.00-4.20 (1H, m), 5.00-5.15(1H, m), 4.70 (1H, d, J=13.8 Hz), 4.90 (1H, d, J=13.8 Hz), 5.47 (1H, s),6.45-6.85 (5H, m), 6.90-7.30 (6H, m).

Example 123

By the reaction and treatment in the same manner as in Example 12 using7-benzyloxychroman-4-carboxylic acid (0.6 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) asstarting materials,7-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(1.2 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.80-2.00 (1H, m), 2.05-2.25(1H, m), 2.85-3.05 (1H, m), 2.94 (6H, s), 3.65-3.75 (1H, m), 3.90-4.05(1H, m), 4.40-4.55 (1H, m), 4.69 (1H, d, J=13.9 Hz), 4.91 (1H, d, J=13.9Hz), 4.99 (2H, s), 6.40-7.45 (16H, m).

Example 124

By the reaction and treatment in the same manner as in Example 17 using7-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(1.0 g) as a starting material,N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)chroman-4-carboxamide(0.54 g) was obtained. melting point: 173.1° C.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.80-2.00 (1H, m), 2.10-2.25(1H, m), 2.94 (6H, s), 2.80-3.05 (1H, m), 3.65-3.75 (1H, m), 3.85-4.00(1H, m), 4.35-4.50 (1H, m), 4.77 (1H, d, J=13.9 Hz), 4.86 (1H, d, J=13.9Hz), 5.87 (1H, s), 6.18 (1H, d, J=2.5 Hz), 6.26 (1H, dd, J=2.5 Hz, 8.3Hz), 6.60-7.30 (9H, m).

Example 125

By the reaction and treatment in the same manner as in Example 12 using8-cyanochroman-4-carboxylic acid (0.7 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.92 g) asstarting materials,8-cyano-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(1.0 g) was obtained. melting point: 178.8° C.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.80-2.30 (2H, m), 2.80-3.10(1H, m) 2.94 (6H, s), 3.65-3.80 (1H, m), 4.10-4.25 (1H, m), 4.55-4.70(1H, m), 4.72 (1H, d, J=13.8 Hz), 4.85 (1H, d, J=13.8 Hz), 6.60-7.50(11H, m).

Example 126

8-Cyano-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(0.9 g) was dissolved in acetone (12.8 mL), and 1 mol/L-aqueous sodiumhydroxide solution (6.4 mL) and 30% aqueous hydrogen peroxide (3.8 mL)were added. The mixture was heated under reflux for 2 hr. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated brine and dried over magnesium sulfate.The solvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give8-carbamoyl-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(21 mg).

MS (ESI) m/z: 472 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.90-2.25 (2H, m), 2.80-3.10(1H, m), 2.94 (6H, s), 3.75-3.90 (1H, m), 4.10-4.30 (1H, m), 4.60-4.80(1H, m), 4.72 (1H, d, J=13.9 Hz), 4.88 (1H, d, J=13.9 Hz), 5.87 (1H,brs), 6.55-6.70 (2H, m), 6.85-7.30 (8H, m), 7.73 (1H, brs), 8.04 (1H,dd, J=1.6, 7.7 Hz).

Example 127

By the reaction and treatment in the same manner as in Example 12 using7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.85 g) was obtained. This compound was dissolved in ethyl acetate, and4 mol/L-HCl/dioxane was added. The precipitated solid was collected byfiltration to giveN-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.85 g). melting point: 165.6° C.

¹H-NMR (DMSO-d₆) δ: 1.19 (6H, d, J=6.9 Hz), 1.30-1.50 (1H, m), 1.70-2.00(3H, m), 2.40-2.75 (2H, m), 2.75-3.05 (1H, m), 2.99 (6H, s), 3.40-3.90(1H, m), 4.75 (1H, d, J=14.7 Hz), 4.92 (1H, d, J=14.7 Hz), 6.70-6.85(1H, m), 6.90-7.35 (10H, m).

Example 128

By the reaction and treatment in the same manner as in Example 12 using7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and[(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (0.54 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidewas obtained. This compound was dissolved in ethyl acetate, and 4mol/L-HCl/dioxane was added. The precipitated solid was collected byfiltration to giveN-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride ½ hydrate (0.52 g). melting point: 125.4° C.

Example 129

By the reaction and treatment in the same manner as in Example 12 using7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and(4-bromophenyl)[(4-dimethylaminophenyl)methyl]amine (0.64 g) as startingmaterials,N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.26 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.40-1.70 (1H, m), 1.75-2.10 (3H, m), 2.55-2.90 (2H,m), 2.95 (6H, s), 3.55-3.70 (1H, m), 4.71 (1H, d, J=14.1 Hz), 4.92 (1H,d, J=14.1 Hz), 6.60-7.20 (9H, m), 7.40-7.60 (2H, m).

Example 130

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine(0.45 g) as starting materials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-8-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.73 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-2.10 (4H, m), 2.55-2.95(3H, m), 2.94 (6H, s), 3.70-3.85 (1H, m), 4.71 (1H, d, J=14.6 Hz), 4.86(1H, d, J=14.6 Hz), 5.01 (2H, s), 6.60-6.85 (4H, m), 7.00-7.45 (11H, m).

Example 131

By the reaction and treatment in the same manner as in Example 17 using5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-8-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.73 g) as a starting material,N-[(4-dimethylaminophenyl)methyl]-8-fluoro-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.19 g) was obtained.

melting point: 209.0° C.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.65-2.05(3H, m), 2.40-2.55 (1H, m), 2.60-2.80 (1H, m), 2.85-3.00 (1H, m), 2.94(6H, s), 3.70-3.80 (1H, m), 4.67 (1H, d, J=14.1 Hz), 4.98 (1H, d, J=14.1Hz), 6.20-6.30 (1H, m), 6.40-6.55 (1H, m), 6.60-6.70 (2H, m), 6.90-7.20(6H, m), 7.61 (1H, s).

Example 132

5-Benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.03 g) was dissolved in dimethylformamide (27 mL), and sodium hydride(0.20 g) was added under ice-cooling. The mixture was stirred at thesame temperature for 30 min. A solution of3-chloromethyl-2,6-dimethoxypyridine (0.95 g) in dimethylformamide (6mL) was added dropwise to the reaction mixture, and the mixture wasstirred at room temperature for 3 hr. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.43 g).

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.40-1.65 (1H, m), 1.75-2.15(3H, m), 2.60-2.80 (2H, m), 2.95-3.15 (1H, m), 3.55-3.75 (1H, m), 3.69(3H, s), 3.89 (3H, s), 4.78 (1H, d, J=14.1 Hz), 4.97 (1H, d, J=14.1 Hz),5.03 (2H, s), 6.25 (1H, d, J=8.0 Hz), 6.63 (1H, d, J=7.7 Hz), 6.72 (1H,d, J=8.0 Hz), 7.06 (1H, t, J=7.9 Hz), 7.14 (1H, d, J=8.3 Hz), 7.25-7.45(6H, m), 7.55 (1H, d, J=8.0 Hz), 8.30 (1H, d, J=2.3 Hz).

Example 133

To a solution of5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) in trifluoroacetic acid (2.4 mL) was added thioanisole (0.49mL), and the mixture was stirred at room temperature for one day. Thereaction mixture was poured into saturated aqueous sodiumhydrogencarbonate and partitioned with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography to giveN-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g).

melting point: 164.0° C.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.35-1.60 (1H, m), 1.75-2.10(3H, m), 2.45-2.70 (2H, m), 2.95-3.15 (1H, m), 3.60-3.75 (1H, m), 3.70(3H, s), 3.89 (3H, s), 4.82 (1H, d, J=14.1 Hz), 4.95 (1H, d, J=14.1 Hz),6.08 (1H, s), 6.26 (1H, d, J=8.1 Hz), 6.44 (1H, d, J=7.8 Hz), 6.51 (1H,d, J=7.8 Hz), 6.87 (1H, t, J=7.8 Hz), 7.16 (1H, d, J=8.1 Hz), 7.34 (1H,dd, J=2.4 Hz, 8.1 Hz), 7.54 (1H, d, J=8.1 Hz), 8.31 (1H, d, J=2.4 Hz).

Example 134

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and[(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.48 g)as starting materials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.39 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.40-2.10 (4H, m), 2.60-3.10(3H, m), 2.94 (6H, s), 3.55-3.70 (1H, m), 4.72 (1H, d, J=14.6 Hz), 4.96(1H, d, J=14.6 Hz), 5.04 (2H, s), 6.50-7.50 (14H, m), 8.30 (1H, d, J=2.4Hz).

Example 135

By the reaction and treatment in the same manner as in Example 17 using5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.39 g) as a starting material,N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(60 mg) was obtained.

MS (ESI) m/z: 444 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.40-1.70 (1H, m), 1.75-2.15(3H, m), 2.50-2.70 (2H, m), 2.95 (6H, s), 3.00-3.10 (1H, m), 3.55-3.70(1H, m), 4.79 (1H, d, J=14.1 Hz), 4.89 (1H, d, J=14.1 Hz), 5.72 (1H, s),6.40-7.30 (9H, m), 8.30 (1H, d, J=2.1 Hz).

Example 136

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine(0.45 g) as starting materials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.6 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.50-1.75 (2H, m), 1.90-2.05(2H, m), 2.11 (3H, s), 2.45-2.60 (1H, m), 2.85-3.05 (2H, m), 2.93 (6H,s), 3.60-3.65 (1H, m), 4.64 (1H, d, J=13.9 Hz), 4.87 (1H, d, J=13.9 Hz),5.02 (2H, s), 6.55-6.70 (3H, m), 6.85-7.45 (12H, m).

Example 137

By the reaction and treatment in the same manner as in Example 133 using5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) as a starting material,N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.34 g) was obtained. melting point: 189.5° C.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.50-1.75 (2H, m), 1.90-2.10(2H, m), 2.09 (3H, s), 2.30-2.50 (1H, m), 2.70-3.00 (2H, m), 2.93 (6H,s), 3.60-3.70 (1H, m), 4.72 (1H, d, J=13.8 Hz), 4.83 (1H, d, J=13.8 Hz),5.72 (1H, s), 6.35-6.75 (4H, m), 7.00-7.30 (6H, m).

Example 138

By the reaction and treatment in the same manner as in Example 132 using5-chloromethyl-2-methoxypyridine (0.63 g) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.87 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.23 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=7.0 Hz), 1.40-1.60 (1H, m), 1.80-2.15(3H, m), 2.65-2.80 (2H, m), 3.00-3.20 (1H, m), 3.60-3.75 (1H, m), 3.92(3H, s), 4.81 (1H, d, J=14.3 Hz), 4.90 (1H, d, J=14.3 Hz), 5.04 (2H, s),6.50-6.80 (3H, m), 7.00-7.50 (7H, m), 7.60-7.70 (1H, m), 7.87 (1H, d,J=2.2 Hz), 8.02 (1H, s), 8.32 (1H, d, J=2.3 Hz).

Example 139

To a solution of5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.23 g) in trifluoroacetic acid (7 mL) was added thioanisole (1.40 mL),and the mixture was stirred at room temperature for one day. Thereaction mixture was partitioned between saturated aqueous sodiumhydrogencarbonate and ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated, and the residue was dissolved in ethyl acetate. Theretowas added 4 mol/L-HCl/dioxane (0.63 mL), and the precipitated solid wascollected by filtration to give5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.43 g).

MS (ESI) m/z: 432 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.35-1.60 (1H, m), 1.70-2.00(3H, m), 2.30-2.60 (2H, m), 3.20-3.45 (1H, m), 3.45-3.70 (1H, m), 3.83(3H, s), 4.60-5.10 (2H, m), 6.45-6.70 (2H, m), 6.80-7.00 (2H, m),7.30-8.25 (4H, m), 8.80 (1H, s).

Example 140

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and(4-isopropylphenyl) [(4-pyrrolidinophenyl)methyl]amine (0.56 g) asstarting materials,N-(4-isopropylphenyl)-7-methoxy-N-[(4-pyrrolidinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.3 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.3 Hz), 1.35-1.60 (1H, m), 1.80-2.10(7H, m), 2.50-2.65 (1H, m), 2.70-2.95 (2H, m), 3.20-3.35 (4H, m), 3.69(3H, s), 3.60-3.80 (1H, m), 4.56 (1H, d, J=13.8 Hz), 5.07 (1H, d, J=13.8Hz), 6.40-7.20 (11H, m).

Example 141

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and{[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g) asstarting materials,N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide½ hydrate (0.28 g) was obtained.

melting point: 110.7° C.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.80-2.10(3H, m), 2.50-2.68 (1H, m), 2.70-3.00 (2H, m), 3.72 (3H, s), 3.65-3.80(1H, m), 4.84 (1H, d, J=14.2 Hz), 5.06 (1H, d, J=14.2 Hz), 6.52 (1H, d,J=2.5 Hz), 6.60-6.70 (1H, m), 6.90-7.10 (3H, m), 7.15-7.50 (8H, m), 7.86(1H, s).

Example 142

2,4-Dimethyl-5-(hydroxymethyl)thiazole (0.65 g) was dissolved inmethylene chloride (15 mL), and methanesulfonyl chloride (0.37 mL) wasadded under ice-cooling. The mixture was stirred at room temperature forone day. The reaction mixture was concentrated, and the residue waspartitioned between water and chloroform. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated. By the reaction and treatment of the obtainedresidue and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.8 g) in the same manner as in Example 132,5-benzyloxy-N-[(2,4-dimethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.64 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.40-1.70 (1H, m), 1.80-2.10(3H, m), 2.00 (3H, s), 2.60-2.80, (2H, m), 2.64 (3H, s), 3.00-3.20 (1H,m), 3.60-3.75 (1H, m), 4.93 (1H, d, J=15.0 Hz), 5.01 (1H, d, J=15.0 Hz),5.04 (2H, s), 6.61 (1H, d, J=7.5 Hz), 6.73 (1H, d, J=8.1 Hz), 7.00-7.50(8H, m), 8.37 (1H, d, J=2.4 Hz).

Example 143

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-[(2,4-dimethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.64 g) as a starting material,N-[(2,4-dimethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride 5/2 hydrate (0.72 g) was obtained.

MS (ESI) m/z: 436 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.27 (6H, d, J=6.9 Hz), 1.10-1.50 (1H, m), 1.65-2.05(3H, m), 1.94 (3H, s), 2.35-2.55 (2H, m), 2.65 (3H, s), 3.10-3.30 (1H,m), 3.45-3.60 (1H, m), 4.92 (1H, d, J=15.4 Hz), 5.02 (1H, d, J=15.4 Hz),6.46 (1H, d, J=7.6 Hz), 6.63 (1H, d, J=7.9 Hz), 6.90 (1H, t, J=7.8 Hz),7.59 (1H, d, J=8.2 Hz), 7.89 (1H, d, J=8.3 Hz), 8.56 (1H, s).

Example 144

By the reaction and treatment in the same manner as in Example 142 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.2 g) and 3-hydroxymethyl-6-(2-methoxyethoxy)pyridine (0.55 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.07 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.80-2.10(3H, m), 2.65-2.80 (2H, m), 2.95-3.15 (1H, m), 3.45 (3H, s), 3.60-3.70(1H, m), 3.70-3.80 (2H, m), 4.40-4.50 (2H, m), 4.80 (1H, d, J=15 Hz),4.90 (1H, d, J=15 Hz), 5.03 (2H, s), 6.57 (1H, d, J=7.8 Hz), 6.73 (1H,d, J=7.8 Hz), 6.78 (1H, d, J=8.4 Hz), 7.06 (1H, t, J=7.8 Hz), 7.17 (1H,d, J=8.4 Hz), 7.20-7.45 (6H, m), 7.60 (1H, dd, J=2.4 Hz, 8.7 Hz), 7.85(1H, d, J=2.1 Hz), 8.33 (1H, d, J=2.4 Hz).

Example 145

By the reaction and treatment in the same manner as in Example 133 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.07 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.72 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.16 (6H, d, J=6.9 Hz), 1.40-1.55 (1H, m), 1.75-2.10(4H, m), 2.50-2.65 (2H, m), 3.00-3.20 (1H, m), 3.45 (3H, s), 3.60-3.70(1H, m), 3.70-3.80 (2H, m), 4.40-4.50 (2H, m), 4.83 (1H, d, J=14.4 Hz),4.90 (1H, d, J=14.4 Hz), 6.30-6.45 (2H, m), 6.70-6.90 (2H, m), 7.10-7.35(2H, m), 7.61 (1H, dd, J=2.4 Hz, 8.5 Hz), 7.86 (1H, d, J=2.2 Hz), 8.34(1H, d, J=2.3 Hz).

Example 146

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.82 g) and[(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) asstarting materials,N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.26 g) was obtained. MS (ESI)m/z: 448 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.0 Hz), 1.29 (3H, t, J=7.6 Hz),1.35-1.55 (1H, m), 1.80-2.10 (3H, m), 2.50-2.65 (1H, m), 2.70-3.00 (2H,m), 2.80 (2H, q, J=7.6 Hz), 3.70 (3H, s), 3.60-3.80 (1H, m), 4.73 (1H,d, J=14.6 Hz), 5.19 (1H, d, J=14.6 Hz), 6.50-6.70 (4H, m), 6.90-7.30(5H, m).

Example 147

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54 g) and{[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g) asstarting materials,5-benzyloxy-N-{[4-(imidazol-1-yl)phenyl]methyl-}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.62 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.2 Hz), 1.40-1.60 (1H, m), 1.80-2.15(3H, m), 2.70-2.80 (2H, m), 2.80-3.00 (1H, m), 3.70-3.85 (1H, m), 4.93(1H, d, J=14.1 Hz), 5.01 (1H, d, J=14.1 Hz), 5.04 (2H, s), 6.65 (1H, d,J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 6.95-7.50 (16H, m), 7.87 (1H, s).

Example 148

By the reaction and treatment in the same manner as in Example 133 using5-benzyloxy-N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.62 g) as a starting material,5-hydroxy-N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.80-2.15(3H, m), 2.50-2.75 (2H, m), 2.85-3.00 (1H, m), 3.70-3.85 (1H, m), 4.97(2H, s), 6.45-6.60 (2H, m), 6.80-7.10 (4H, m), 7.15-7.45 (7H, m), 7.89(1H, s).

Example 149

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and(4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.54 g) as startingmaterials,N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.81 g) was obtained.

¹H-NMR (CDCl₃) δ: (0.92 (3H, t, J=7.4 Hz), 1.26-1.37 (2H, m), 1.50-1.52(1H, m), 1.55-1.64 (2H, m), 1.89-1.91 (1H, m), 1.95-2.04 (2H, m), 2.58(2H, t, J=7.4 Hz), 2.65-2.67 (1H, m), 2.82-2.85 (1H, m), 2.94 (6H, s),3.70-3.75 (1H, m), 4.72 (1H, d, J=13.9 Hz), 4.93 (1H, d, J=13.9 Hz),6.63 (2H, m), 6.94-7.13 (10H, m).

Example 150

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and(4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.59 g) as startingmaterials,N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.60 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.8 Hz), 1.47-1.51 (1H, m), 1.87-1.91(1H, m), 1.94-2.05 (2H, m), 2.63 (2H, q, J=7.8 Hz), 2.59-2.67 (1H, m),2.80-2.85 (1H, m), 3.16 (4H, t, J=4.8 Hz), 3.71-3.76 (1H, m), 3.87 (4H,t, J=4.8 Hz), 4.75 (1H, d, J=13.8 Hz), 4.94 (1H, d, J=13.8 Hz),6.81-6.84 (2H, m), 6.95-7.17 (10H, m).

Example 151

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and(4-ethylphenyl)(2-piperidinoethyl)amine (0.47 g) as starting materials,N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.65 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22-1.28 (4H, m), 1.43-1.60 (7H, m), 1.94-2.01 (2H,m), 2.39-2.56 (6H, m), 2.63-2.70 (3H, m), 2.78-2.90 (1H, m), 3.61-3.75(2H, m), 4.10-4.17 (1H, m), 7.00-7.13 (3H, m), 7.18-7.28 (5H, m).

Example 152

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and[(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.49 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.54 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.45-1.54 (1H, m), 1.86-2.02 (3H, m), 2.63-2.71 (1H,m), 2.80-2.91 (1H, m), 2.94 (6H, s), 3.66-3.71 (1H, m), 3.91 (3H, s),4.71 (1H, d, J=13.9 Hz), 4.92 (1H, d, J=13.9 Hz), 6.62-6.66 (3H, m),6.95-6.98 (1H, m), 7.03-7.12 (5H, m), 7.19 (1H, dd, J=2.7, 8.7 Hz), 7.89(1H, d, J=2.5 Hz).

Example 153

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and[(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.66 g) as startingmaterials,N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) was obtained. melting point: 120-121° C.

Example 154

By the reaction and treatment in the same manner as in Example 17 usingN-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.39 g) as a starting material,N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g) was obtained. melting point: 156° C.

Example 155

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.49 g) asstarting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.1 g) was obtained. By the reaction and treatment in the same manneras in Example 105 using this compound,N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.73 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.43-1.46 (1H, m), 1.81-2.05(5H, m), 2.21-2.27 (8H, m), 2.57-2.62 (2H, m), 2.92 (1H, sept, J=6.9Hz), 3.68-3.73 (1H, m), 4.13 (2H, t, J=6.9 Hz), 4.61 (1H, d, J=14.3 Hz),4.83 (1H, d, J=14.3 Hz), 6.36 (1H, d, J=7.8 Hz), 6.43 (1H, d, J=7.8 Hz),6.81 (1H, t, J=7.8 Hz), 7.06 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz),7.36 (1H, s), 7.42 (1H, s).

Example 156

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g) and(4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.56 g) as startingmaterials,5-benzyloxy-N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound,N-(4-ethylphenyl)-5-hydroxy-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.51 g) was obtained. melting point: 200° C.

Example 157

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.66 g) and(4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.55 g) as startingmaterials,5-benzyloxy-N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.98 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound,N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) was obtained. melting point: 138° C.

Example 158

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.72 g) and(4-ethylphenyl) (2-piperidinoethyl)amine (0.50 g) as starting materials,5-benzyloxy-N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.19 g) was obtained. By the reaction and treatment in the same manneras in Example 105 using this compound,N-(4-ethylphenyl)-5-hydroxy-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.35-2.00 (9H, m), 2.42-2.57 (7H, m), 2.67 (2H, q,J=7.6 Hz), 3.48 (1H, s), 3.65-3.75 (3H, m), 4.06-4.13 (1H, m), 6.34 (1H,d, J=7.8 Hz), 6.66 (1H, d, J=7.8 Hz), 6.81 (1H, d, J=7.8 Hz), 7.21-7.26(4H, m).

Example 159

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.94 g) and[(3,4-dibenzyloxyphenyl)methyl](4-isopropylphenyl)amine (2.5 g) asstarting materials,5-benzyloxy-N-[(3,4-dibenzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.64 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound,N-[(3,4-dihydroxyphenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.35 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, m), 137-1.42 (1H, m), 1.82-1.97 (6H, m),2.35-2.43 (1H, m), 2.48-2.55 (1H, m), 2.89 (1H, sept, J=6.9 Hz),3.71-3.76 (1H, m), 4.70 (1H, d, J=13.8 Hz), 4.82 (1H, d, J=13.8 Hz),6.30 (1H, dd, J=2.0, 8.0 Hz), 6.47 (1H, d, J=8.0 Hz), 6.61 (2H, t, J=7.7Hz), 6.90-6.98 (4H, m), 7.17 (2H, d, J=8.4 Hz).

Example 160

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.59 g) and[(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.58 g) as startingmaterials,5-benzyloxy-N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.74 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound,5-hydroxy-N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained. melting point: 241-243° C.

Example 161

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and[(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.91 g) asstarting materials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.35 g) was obtained. By the reaction and treatment in the same manneras in Example 105 using this compound,N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.34 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.45-1.5 (1H, m), 1.81-2.05 (3H, m), 2.59-2.62 (2H,m), 2.94 (6H, s), 3.65-3.70 (1H, m), 3.92 (3H, m), 4.83 (2H, s), 6.38(1H, d, J=7.8 Hz), 6.46 (1H, d, J=7.8 Hz), 6.64-6.71 (3H, m), 6.82 (1H,d, J=7.8 Hz), 7.05-7.09 (2H, m), 7.19-7.22 (2H, m), 7.91 (1H, brs).

Example 162

Aniline (93.1 mg) was dissolved in dichloroethane (5 mL), and4-dimethylaminobenzaldehyde (149 mg), acetic acid (0.06 mL) and sodiumtriacetoxy borohydride (0.42 g) were added. The mixture was stirred atroom temperature for one day. Saturated aqueous sodium hydrogencarbonate(2 mL) was added to the reaction solution, and the mixture was stirredfor a while, after which the aqueous layer was absorbed using adiatomaceous earth column. The obtained organic layer was concentratedunder reduced pressure, and dichloromethane (5 mL) was added to theresidue. To this solution was added a solution of7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid chloride (0.23g) in dichloromethane (5 mL), and the mixture was stirred at roomtemperature for one day. Saturated aqueous sodium hydrogencarbonate (2mL) was added to the reaction solution. The mixture was stirred for awhile, after which the aqueous layer was absorbed using a diatomaceousearth column. The obtained organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to giveN-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(260 mg).

¹H-NMR (CDCl₃) δ: 1.42-1.54 (1H, m), 1.83-2.04 (3H, m), 2.53-2.86 (2H,m), 2.93 (6H, s), 3.65-3.72 (1H, m), 3.70 (3H, s), 4.62 (1H, d, J=13.9Hz), 5.08 (1H, d, J=13.9 Hz), 6.53 (1H, d, J=2.5 Hz), 6.62-6.69 (3H, m),6.95 (1H, d, J=8.4 Hz), 7.05-7.13 (3H, m), 7.30-7.34 (4H, m).

Example 163

By the reaction and treatment in the same manner as in Example 162 using4-methoxyaniline (0.12 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.43-1.55 (1H, m), 1.80-2.05 (3H, m), 2.56-2.62 (1H,m), 2.70-2.85 (1H, m), 2.93 (6H, s), 3.66-3.70 (1H, m), 3.70 (3H, s),3.79 (3H, s), 4.57 (1H, d, J=13.8 Hz), 5.05 (1H, d, J=13.8 Hz), 6.51(1H, d, J=2.5 Hz), 6.62-6.69 (3H, m), 6.81-6.85 (2H, m), 6.93-6.97 (3H,m), 7.09-7.13 (2H, m).

Example 164

By the reaction and treatment in the same manner as in Example 162 using4-cyclohexylaniline (0.18 g) as a starting material instead of aniline,N-(4-cyclohexylphenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.088 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.34-2.03 (14H, m), 2.44-2.61 (2H, m), 2.71-2.85 (1H,m), 2.93 (6H, s), 3.68-3.72 (1H, m), 3.68 (3H, s), 4.58 (1H, d, J=13.9Hz), 5.06 (1H, d, J=13.9 Hz), 6.51 (1H, d, J=2.5 Hz)., 6.63-6.68 (3H,m), 6.93-6.98 (3H, m), 7.12-7.16 (4H, m).

Example 165

By the reaction and treatment in the same manner as in Example 162 using3,4-dimethylaniline (0.12 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(3,4-dimethylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.29 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.35-1.51 (1H, m), 1.86-2.02 (3H, m), 2.21 (3H, s),2.23 (3H, s), 2.51-2.63 (1H, m), 2.69-2.83 (1H, m), 2.93 (6H, s), 3.69(3H, s), 3.69-3.74 (1H, m), 4.50-4.65 (1H, m), 4.96-5.08 (1H, m), 6.52(1H, d, J=2.4 Hz), 6.62-6.68 (3H, m), 6.73-6.76 (1H, m), 6.86 (1H, d,J=1.7 Hz), 6.94 (1H, d, J=8.5 Hz), 7.05 (1H, d, J=8.5 Hz), 7.06-7.12(2H, m).

Example 166

By the reaction and treatment in the same manner as in Example 162 using3,4-dichloroaniline (0.16 g) as a starting material instead of aniline,N-(3,4-dichlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.14 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.56 (1H, m), 1.80-2.03 (3H, m), 2.55-2.82 (2H,m), 2.94 (6H, s), 3.60-3.69 (1H, m), 3.71 (3H, s), 3.58-3.70 (1H, m),4.97-5.05 (1H, m), 6.45-6.46 (1H, m), 6.62-6.71 (3H, m), 6.85-6.88 (1H,m), 6.96-6.98 (1H, m), 7.05-7.09 (2H, m), 7.20 (1H, brs), 7.39 (1H, d,J=8.4 Hz).

Example 167

N-(4-Isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.2 g) was dissolved in ethanol (8.1 mL), and stannic chloride (1.5 g)and conc. hydrochloric acid (2.7 mL) were added. The mixture was heatedunder reflux for 3 hr. The reaction mixture was concentrated underreduced pressure, and the residue was partitioned between water andethyl acetate. The organic layer was washed with saturated aqueoussodium hydrogencarbonate and dried over magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained solid wasrecrystallized from a mixed solvent of chloroform and diisopropyl etherto giveN-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.0 g).

melting point: 115-117° C.

Example 168

By the reaction and treatment in the same manner as in Example 162 using4-morpholinoaniline (0.18 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-morpholinophenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.40-1.47 (1H, m), 1.82-2.05 (3H, m), 2.56-2.84 (2H,m), 2.93 (6H, s), 3.13-3.16 (4H, m), 3.66-3.73 (1H, m), 3.69 (3H, s),3.83-3.86 (4H, m), 4.57 (1H, d, J=13.8 Hz), 5.05 (1H, d, J=13.8 Hz),6.52 (1H, s), 6.62-6.68 (3H, m), 6.80-6.83 (2H, m), 6.93-7.02 (3H, m),7.13 (2H, d, J=8.4 Hz).

Example 169

By the reaction and treatment in the same manner as in Example 162 using2,6-dimethylaniline (0.12 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(2,6-dimethylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.16 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24-1.28 (1H, m), 1.89-2.10 (3H, m), 2.10 (6H, s),2.40-2.45 (1H, m), 2.76-2.83 (1H, m), 2.90 (6H, s), 3.72-3.78 (3H, m),3.77 (3H, s), 6.49 (1H, s), 6.66 (2H, d, J8.6=Hz), 6.80-6.88 (4H, m),7.00-7.05 (2H, m), 7.08-7.11 (1H, m).

Example 170

By the reaction and treatment in the same manner as in Example 162 using3,4-dimethoxyaniline (0.15 g) as a starting material instead of aniline,N-(3,4-dimethoxyphenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.18 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.40-1.51 (1H, m), 1.82-2.05 (3H, m), 2.56-2.62 (1H,m), 2.72-2.81 (1H, m), 2.93 (6H, s), 3.66-3.74 (1H, m), 3.69 (6H, s),3.87 (3H, s), 4.53-4.63 (1H, m), 5.00-5.10 (1H, m), 6.45 (1H, d, J=2.1Hz), 6.52 (1H, d, J=2.1 Hz), 6.63-6.69 (4H, m), 6.78 (1H, d, J=8.7 Hz),6.95 (1H, d, J=8.4 Hz), 7.12 (2H, d, J=8.7 Hz).

Example 171

By the reaction and treatment in the same manner as in Example 162 using3,4,5-trimethoxyaniline (0.18 g) as a starting material instead ofaniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.22 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.59 (1H, m), 1.80-2.05 (3H, m), 2.52-2.64 (1H,m), 2.71-2.85 (1H, m), 2.92 (6H, s), 3.67-3.85 (13H, m), 4.58 (1H, d,J=13.8 Hz), 5.04 (1H, d, J=13.8 Hz), 6.22 (2H, s), 6.51 (1H, d, J=2.4Hz), 6.63-69.73 (3H, m), 6.96 (1H, d, J=8.4 Hz), 7.14-7.16 (2H, m).

Example 172

By the reaction and treatment in the same manner as in Example 162 using4-cyanoaniline (0.12 g) as a starting material instead of aniline,N-(4-cyanophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.097 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.20-1.27 (1H, m), 1.79-2.05 (3H, m), 2.55-2.65 (1H,m), 2.70-2.84 (1H, m), 2.94 (6H, s), 3.55-3.66 (1H, m), 3.72 (3H, s),4.72 (1H, d, J=14.1 Hz), 5.03 (1H, d, J=14.1 Hz), 6.47 (1H, d, J=2.4Hz), 6.62 (2H, d, J=8.1 Hz), 6.70 (1H, dd, J=2.4, 8.1 Hz), 6.97 (1H, d,J=8.1 Hz), 7.05 (2H, d, J=8.1 Hz), 7.18-7.20 (2H, m), 7.63-7.66 (2H, m).

Example 173

By the reaction and treatment in the same manner as in Example 162 using2-fluoroaniline (0.11 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(2-fluorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.54 (1H, m), 1.79-2.08 (3H, m), 2.55-2.61 (1H,m), 2.71-2.85 (1H, m), 2.92 (6H, s), 3.58-3.68 (1H, m), 3.69 (1.5H, s),3.76 (1.5H, s), 4.16 (0.5H, d, J=14.1 Hz), 4.39 (0.5H, d, J=14.1 Hz),5.28 (0.5H, d, J=14.1 Hz), 5.52 (0.5H, d, J=14.1 Hz), 6.48-6.49 (0.5H,m), 6.59-6.70 (3.5H, m), 6.93-7.25 (7H, m).

Example 174

By the reaction and treatment in the same manner as in Example 162 using3-fluoroaniline (0.11 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(3-fluorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.26 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.50 (1H, m), 1.86-2.02 (3H, m), 2.56-2.83 (2H,m), 2.93 (6H, s), 3.65-3.69 (1H, m), 3.70 (3H, s), 4.62 (1H, d, J=13.9Hz), 5.04 (1H, d, J=13.9 Hz), 6.48 (1H, d, J=2.4 Hz), 6.62-6.70 (3H, m),6.80-7.11 (6H, m), 7.26-7.31 (1H, m).

Example 175

By the reaction and treatment in the same manner as in Example 162 using4-fluoroaniline (0.11 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(4-fluorophenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.38-1.56 (1H, m), 1.79-2.05 (3H, m), 2.52-2.65 (1H,m), 2.71-2.82 (1H, m), 2.93 (6H, s), 3.61-3.67 (1H, m), 3.71 (3H, s),4.60 (1H, d, J=13.8 Hz), 5.04 (1H, d, J=13.8 Hz), 6.49 (1H, d, J=2.4Hz), 6.61-6.70 (3H, m), 6.94-7.10 (7H, m).

Example 176

By the reaction and treatment in the same manner as in Example 162 using3-cyanoaniline (0.12 g) as a starting material instead of aniline,N-(3-cyanophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.14 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.51 (1H, m), 1.79-2.05 (3H, m), 2.54-2.83 (2H,m), 2.94 (6H, s), 3.48-3.62 (1H, m), 3.73 (3H, s), 4.67 (1H, d, J=14.1Hz), 5.01 (1H, d, J=14.1 Hz), 6.47 (1H, d, J=2.4 Hz), 6.62 (2H, d, J=8.7Hz), 6.70 (1H, dd, J=2.4, 8.1 Hz), 6.97 (1H, d, J=8.1 Hz), 7.05 (2H, d,J=8.7 Hz), 7.26-7.35 (2H, m), 7.46 (1H, t, J=7.8 Hz), 7.60 (1H, d, J=7.8Hz).

Example 177

By the reaction and treatment in the same manner as in Example 162 using2-chloroaniline (0.12 g) as a starting material instead of aniline,N-(2-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.24 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.40-1.55 (1H, m), 1.73-2.12 (3H, m), 2.50-2.65 (1H,m), 2.70-2.84 (1H, m), 2.93 (6H, s), 3.40-3.52 (1H, m), 3.64 (1.5H, s),3.76 (1.5H, s), 3.85 (0.5H, d, J=14.0 Hz), 3.97 (0.5H, d, J=14.1 Hz)5.64 (0.5H, d, J=14.1 Hz), 5.80 (0.5H, d, J=14.0 Hz), 6.46-6.47 (0.5H,m), 6.60-6.71 (3H, m), 6.81-6.82 (1H, m), 6.88-6.98 (1.5H, m), 7.04-7.16(3H, m), 7.24-7.32 (1H, m), 7.50-7.55 (1H, m).

Example 178

By the reaction and treatment in the same manner as in Example 162 using3-chloroaniline (0.12 g) as a starting material instead of aniline,N-(3-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.51 (1H, m), 1.79-2.05 (3H, m), 2.54-2.83 (2H,m), 2.93 (6H, s), 3.63-3.68 (1H, m), 3.69 (3H, s), 4.62 (1H, d, J=14.0Hz), 5.03 (1H, d, J=14.0 Hz), 6.48 (1H, d, J=2.5 Hz), 6.62-6.70 (3H, m),6.91-7.11 (6H, m), 7.23-7.29 (1H, m).

Example 179

By the reaction and treatment in the same manner as in Example 162 using4-chloroaniline (0.12 g) as a starting material instead of aniline,N-(4-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.30 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.45-1.53 (1H, m), 1.78-2.03 (3H, m), 2.55-2.82 (2H,m), 2.93 (6H, s), 3.61-3.68 (1H, m), 3.71 (3H, s), 4.61 (1H, d, J=13.9Hz), 5.03 (1H, d, J=13.9 Hz), 6.48 (1H, d, J=2.4 Hz), 6.61-6.70 (3H, m),6.94-7.07 (3H, m), 7.07-7.10 (2H, m), 7.21-7.32 (2H, m).

Example 180

By the reaction and treatment in the same manner as in Example 162 usingo-toluidine (0.11 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(2-methylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.22 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.37-1.50 (1H, m), 1.81-2.10 (3H, m), 2.26 (3H, s),2.53-2.61 (1H, m), 2.70-2.82 (1H, m), 2.93 (6H, s), 2.42-2.53 (1H, m),3.61 (1.8H, s), 3.74 (1.2H, s), 3.97 (0.6H, d, J=13.5 Hz), 4.33 (0.4H,d, J=13.5 Hz), 5.19 (0.4H, d, J=13.5 Hz), 5.58 (0.6H, d, J=13.5 Hz),6.48-7.26 (11H, m).

Example 181

By the reaction and treatment in the same manner as in Example 162 usingm-toluidine (0.11 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(3-methylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.30-1.40 (1H, m), 1.80-1.95 (3H, m), 2.29 (3H, s),2.50-2.72 (2H, m), 2.86 (6H, s), 3.61-3.67 (1H, m), 3.67 (3H, s), 4.64(1H, d, J=13.9 Hz), 4.83 (1H, d, J=13.9 Hz), 6.45 (1H, d, J=2.4 Hz),6.63 (2H, d, J=8.4 Hz), 6.70 (1H, dd, J=2.4, 8.4 Hz), 6.92-7.02 (4H, m),7.08 (1H, s), 7.15 (1H, d, J=7.5 Hz), 7.26-7.31 (1H, m).

Example 182

By the reaction and treatment in the same manner as in Example 162 usingp-toluidine (0.11 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.27 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.30-1.40 (1H, m), 1.79-1.97 (3H, m), 2.29 (3H, s),2.48-2.68 (2H, m), 2.86 (6H, s), 3.57-3.62 (1H, m), 3.67 (3H, s), 4.63(1H, d, J=13.9 Hz), 4.83 (1H, d, J=13.9 Hz), 6.45-6.46 (1H, m),6.60-6.70 (3H, m), 6.95-7.25 (7H, m).

Example 183

By the reaction and treatment in the same manner as in Example 162 using2-isopropylaniline (0.14 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(2-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.01-1.05 (3H, m), 1.13-1.23 (3H, m), 1.23-1.40 (1H,m), 1.71-1.98 (3H, m), 2.51-2.70 (3H, m), 2.85 (6H, m), 2.92-3.05 (0.5H,m), 3.13-3.23 (0.5H, m), 3.61 (1.5H, s), 3.70 (1.5H, s), 4.09 (0.5H, d,J=14.1 Hz), 4.26 (0.5H, d, J=14.1 Hz), 5.09 (0.5H, d, J=14.1 Hz), 5.32(0.5H, d, J=14.1 Hz), 6.45 (1H, d, J=2.4 Hz), 6.63 (2H, d, J=8.6 Hz),6.64-6.73 (1H, m), 6.85-7.04 (4H, m), 7.14-7.18 (1H, m), 7.31-7.39 (1H,m), 7.45-7.49 (1H, m).

Example 184

By the reaction and treatment in the same manner as in Example 162 using3-isopropylaniline (0.14 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(3-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.28 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.07-1.12 (6H, m), 1.27-1.42 (1H, m), 1.82-1.90 (3H,m), 2.49-2.68 (3H, m), 2.86 (6H, s), 3.56-3.60 (1H, m), 3.66 (3H, s),4.60 (1H, d, J=14.1 Hz), 4.92 (1H, d, J=14.1 Hz), 6.44 (1H, d, J=2.4Hz), 6.62-6.71 (3H, m), 6.93-7.02 (5H, m), 7.20 (1H, d, J=7.8 Hz), 7.32(1H, d, J=7.8 Hz).

Example 185

By the reaction and treatment in the same manner as in Example 162 using2-methoxyaniline (0.12 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl)]-7-methoxy-N-(2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.29 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.32-1.42 (1H, m), 1.74-1.92 (3H, m), 2.49-2.68 (2H,m), 2.85 (6H, s), 3.47-3.51 (1H, m), 3.63 (1.5H, s), 3.71 (1.5H, s),3.82 (1.5H, s), 3.84 (1.5H, s), 3.99 (0.5H, d, J=14.1 Hz), 4.11 (0.5H,d, J=14.1 Hz), 5.17 (0.5H, d, J=14.1 Hz), 5.33 (0.5H, d, J=14.1 Hz),6.46 (0.5H, d, J=2.4 Hz), 6.60-6.70 (3.5H, m), 6.89-7.03 (5H, m), 7.16(1H, d, J=8.4 Hz), 7.30-7.35 (1H, m).

Example 186

By the reaction and treatment in the same manner as in Example 162 using3-methoxyaniline (0.12 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(3-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.20 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.33-1.42 (1H, m), 1.81-1.96 (3H, m), 2.55-2.70 (2H,m), 2.86 (6H, s), 3.65 (3H, s), 3.70 (3H, s), 3.61-3.73 (1H, m), 4.62(1H, d, J=14.2 Hz), 4.91 (H, d, J=14.2 Hz), 6.46 (H, d, J=2.4 Hz),6.46-6.76 (5H, m), 6.91-7.02 (4H, m), 7.32 (1H, t, J=8.0 Hz).

Example 187

By the reaction and treatment in the same manner as in Example 162 using4-ethoxyaniline (0.14 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(4-ethoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.28 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.25-1.40 (1H, m), 1.27 (3H, t, J=6.9 Hz), 1.78-1.94(3H, m), 2.54-2.64 (2H, m), 2.86 (6H, s), 3.57-3.63 (1H, m), 3.67 (3H,s), 3.99 (2H, q, J=6.9 Hz), 4.58 (1H, d, J=14.1 Hz), 4.87 (1H, d, J=14.1Hz), 6.44 (1H, d, J=2.4 Hz), 6.63 (2H, d, J=8.4 Hz), 6.70 (1H, dd,J=2.4, 8.4 Hz), 6.91-7.09 (7H, m).

Example 188

By the reaction and treatment in the same manner as in Example 162 using4-bromoaniline (0.17 g) as a starting material instead of aniline,N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.25 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.36-1.47 (1H, m), 1.79-1.94 (3H, m), 2.51-2.64 (2H,m), 2.86 (6H, s), 3.55-3.60 (1H, m), 3.67 (3H, s), 4.65 (1H, d, J=14.1Hz), 4.88 (1H, d, J=14.1 Hz), 6.44 (1H, d, J=2.4 Hz), 6.63 (2H, d, J=8.7Hz), 6.67-6.73 (1H, m), 6.95-7.03 (3H, m), 7.16 (2H, d, J=8.4 Hz), 7.62(2H, d, J=8.4 Hz).

Example 189

By the reaction and treatment in the same manner as in Example 162 using2,4-dichloroaniline (0.16 g) as a starting material instead of aniline,N-(2,4-dichlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.42-1.56 (1H, m), 1.75-1.86 (1H, m), 1.97-2.05 (2H,m), 2.56-2.63 (1H, m), 2.72-2.82 (1H, m), 2.94 (6H, s), 3.40-3.48 (1H,m), 3.65 (1.5H, s), 3.75 (1.5H, s), 3.82 (0.5H, d, J=14.0 Hz), 3.92(0.5H, d, J=14.1 Hz), 5.63 (0.5H, d, J=14.1 Hz), 5.78 (0.5H, d, J=14.0Hz), 6.41-6.42 (0.5H, m), 6.60-6.82 (4.5H, m), 6.94-7.15 (4H, m),7.54-7.55 (1H, m).

Example 190

By the reaction and treatment in the same manner as in Example 162 using2,4-dimethylaniline (0.12 g) as a starting material instead of aniline,N-[(4-dimethylaminophenyl)methyl]-N-(2,4-dimethylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.29 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.40-1.50 (1H, m), 1.80-2.07 (3H, m), 2.20 (1.8H, s),2.22 (1.2H, s), 2.23 (1.8H, s), 2.30 (1.2H, s), 1.52-1.60 (1H, m),1.72-1.81 (1H, m), 2.92 (6H, m), 3.45-3.57 (1H, m), 3.60 (1.8H, s), 3.73(1.2H, s), 3.95 (0.6H, d, J=13.6 Hz), 4.30 (0.4H, d, J=13.7 Hz), 5.24(0.4H, d, J=13.7 Hz), 5.56 (0.6H, d, J=13.6 Hz), 6.48-7.17 (10H, m).

Example 191

By the reaction and treatment in the same manner as in Example 162 using2,4,6-trimethylaniline (0.14 g) as a starting material instead ofaniline,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(2,4,6-trimethylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.095 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.37-1.49 (1H, m), 1.69-1.93 (3H, m), 1.90 (3H, s),2.12 (3H, s), 2.28 (3H, s), 2.52-2.62 (1H, m), 2.73-2.80 (1H, m), 2.91(6H, s), 3.41-3.45 (1H, m), 3.69 (3H, s), 4.17 (1H, d, J=13.5 Hz), 5.5(1H, d, J=13.5 Hz), 6.53-6.69 (4H, m), 6.80-6.84 (1H, m), 6.94 (2H, d,J=8.1 Hz), 7.11-7.25 (2H, m).

Example 192

By the reaction and treatment in the same manner as in Example 162 using2,4-dimethoxyaniline (0.15 g) as a starting material instead of aniline,N-(2,4-dimethoxyphenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.39 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.37-1.45 (1H, m), 1.74-1.93 (3H, m), 2.55-2.63 (2H,m), 2.85 (3H, s), 2.86 (3H, s), 3.50-3.54 (1H, m), 3.63-3.83 (9H, m),3.89 (0.5H, d, J=14.1 Hz), 3.99-4.05 (0.5H, m), 5.16 (0.5H, d, J=14.2Hz), 5.32 (0.5H, d, J=14.1 Hz), 6.44-6.70 (6H, m), 6.77-6.81 (1H, m),6.92-7.03 (3H, m).

Example 193

By the reaction and treatment in the same manner as in Example 162 using5-amino-1,3-dioxaindane (0.14 g) as a starting material instead ofaniline,N-(1,3-dioxaindan-5-yl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.12 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.37-1.43 (1H, m), 1.79-1.94 (3H, m), 2.55-2.64 (2H,m), 2.87 (6H, s), 3.64-3.66 (1H, m), 3.67 (3H, s), 4.55-4.62 (1H, m),4.82-4.89 (1H, m), 6.04-6.06 (2H, m), 6.45 (1H, d, J=2.4 Hz), 6.57-6.72(4H, m), 6.82-6.83 (1H, m), 6.89-7.03 (4H, m).

Example 194

By the reaction and treatment in the same manner as in Example 162 using4-dimethylaminoaniline (0.14 g) as a starting material instead ofaniline,N-(4-dimethylaminophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.16 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.30-1.40 (1H, m), 1.78-1.94 (3H, m), 2.56-2.64 (2H,m), 2.87 (12H, s), 3.64-3.68 (1H, m), 3.66 (3H, s), 4.56 (1H, d, J=14.1Hz), 4.85 (1H, d, J=14.1 Hz), 6.45 (1H, d, J=2.4 Hz), 6.62-6.71 (5H, m),6.93-7.02 (5H, m).

Example 195

N-[(4-Aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(6.47 g) was stirred using di-tert-butyl dicarbonate (in an amount as asolvent) at 80° C. for 2 hr. The reaction mixture was partitionedbetween saturated aqueous sodium hydrogencarbonate and ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated, and the residuewas purified by silica gel column chromatography to give a solid (6.55g). From the solid, 2.0 g was dissolved in dimethylformamide (3 mL), andsodium hydride (0.34 g) was added under cooling. The mixture was stirredat the same temperature for 30 min, and methyl iodide (0.28 mL) wasadded to the reaction mixture, which was followed by stirring for 1 hr.The reaction mixture was poured into iced water and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was dissolved in 4 mol/L-HCL/dioxane(5 mL). The mixture was stirred at room temperature for one day. Thereaction mixture was partitioned between saturated aqueous sodiumhydrogencarbonate and ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby silica gel column chromatography to giveN-(4-isopropylphenyl)-7-methoxy-N-[(4-methylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.45 g).

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, d, J=6.9 Hz), 1.19 (3H, d, J=6.9 Hz),1.30-1.39 (1H, m), 1.80-1.94 (3H, m), 2.50-2.64 (2H, m), 2.61 (3H, s),2.88 (1H, sept, J=6.9 Hz), 3.55-3.60 (1H, m), 3.67 (3H, s), 4.56 (1H, d,J=14.1 Hz), 4.87 (1H, d, J=14.1 Hz), 6.43-6.46 (3H, m), 6.68-6.72 (1H,m), 6.91-6.97 (3H, m), 7.10 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz).

Example 196

By the reaction and treatment in the same manner as in Example 162 usingN-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) and ethyl iodide (0.07 mL) as starting materials,N-[(4-ethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.29 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.13-1.18 (9H, m), 1.31-1.35 (1H, m), 1.83-1.93 (3H,m), 2.49-2.70 (2H, m), 2.86 (1H, sept, J=6.9 Hz), 2.99 (2H, q, J=7.1Hz), 3.39-3.58 (1H, m), 3.68 (3H, s), 4.57 (1H, d, J=14.2 Hz), 4.90 (1H,d, J=14.2 Hz), 6.47-6.50 (3H, m), 6.69 (1H, dd, J=2.5, 8.4 Hz),6.92-6.96 (3H, m), 7.11 (2H, d, J=8.3 Hz), 7.26 (2H, d, J=8.3 Hz).

Example 197

By the reaction and treatment in the same manner as in Example 162 usingN-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) and benzyl bromide (0.1 mL) as starting materials,N-[(4-benzylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.13 g) was obtained.

melting point: 135-138° C.

Example 198

By the reaction and treatment in the same manner as in Example 162 usingN-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) and pentyl bromide (0.14 mL) as starting materials,N-(4-isopropylphenyl)-7-methoxy-N-[(4-pentylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.19 g) was obtained.

¹H-NMR (CDCl₃) δ: (0.90-(0.95 (3H, m), 1.23 (6H, d, J=6.9 Hz), 1.36-1.64(7H, m), 1.85-2.04 (3H, m), 2.54-2.61 (1H, m), 2.71-2.92 (2H, m), 3.08(2H, t, J=7.1 Hz), 3.59 (1H, brs), 3.66-3.71 (1H, m), 3.69 (3H, s), 4.55(1H, d, J=13.9 Hz), 5.05 (1H, d, J=13.9 Hz), 6.49-6.53 (3H, m), 6.67(1H, dd, J=2.6, 8.3 Hz), 6.93-6.98 (3H, m), 7.05-7.08 (2H, m), 7.16 (2H,d, J=8.3 Hz).

Example 199

N-(4-Isopropylphenyl)-7-methoxy-N-[(4-methylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was dissolved in ethanol (8 mL), and butyl aldehyde (250 mg)and sodium cyanoborohydride (0.22 g) were added. Acetic acid was addedto this solution to pH 5-6, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was partitioned betweensaturated aqueous sodium hydrogencarbonate and ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure and theobtained residue was purified by silica gel column chromatography togiveN-{[4-(butylmethylamino)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.51 g).

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.3 Hz), 1.22 (6H, d, J=6.9 Hz),1.22-1.57 (5H, m), 1.87-2.02 (3H, m), 2.52-2.60 (1H, m), 2.73-2.86 (2H,m), 2.89 (3H, s), 3.25 (2H, t, J=6.9 Hz), 3.67 (3H, s), 3.67-3.73 (1H,m), 4.54 (1H, d, J=13.8 Hz), 5.08 (1H, d, J=13.8 Hz), 6.53 (1H, d, J=2.4Hz), 6.58 (2H, d, J=8.7 Hz), 6.65 (1H, dd, J=2.4, 8.4 Hz), 6.92 (1H, d,J=8.4 Hz), 6.99 (2H, d, J=8.4 Hz), 7.11-7.22 (4H, m).

Example 200

7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.47 g) and(4-bromophenyl)[(4-dimethylaminophenyl)methyl]-amine (0.70 g) asstarting materials were reacted and treated in the same manner as inExample 12. The obtained solid was dissolved in ethyl acetate (4 mL).Thereto was added 4 mol/L-HCl/ethyl acetate (0.35 mL), and theprecipitated solid was collected by filtration to giveN-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.65 g). melting point: 104-113° C.

Example 201

By the reaction and treatment in the same manner as in Example 200 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.50 g) and[(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (0.62 g) asstarting materials,N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.79 g) was obtained. melting point: 152° C.

Example 202

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57 g) and[(4-dimethylaminophenyl)methyl]-4-methoxyphenyl)amine (0.51 g) asstarting materials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound,N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained, melting point: 195-197° C.

Example 203

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57 g) and[(4-dimethylaminophenyl)methyl]phenylamine (0.61 g) as startingmaterials,5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.80 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound,N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.083 g) was obtained. melting point: 138-143° C.

Example 204

By the reaction and treatment in the same manner as in Example 132 using5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.65 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as startingmaterials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) was obtained. By the reaction and treatment in the same manneras in Example 133 using this compound (0.51 g),5-hydroxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.22 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.38-1.48 (1H, m), 1.82-1.90(1H, m), 1.92-2.00 (2H, m), 2.58-2.60 (2H, m), 2.68 (3H, s), 2.89 (1H,sept, J=6.9 Hz), 3.80-3.84 (1H, m), 5.01 (2H, s), 6.23 (1H, d, J=7.8Hz), 6.48 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=7.8 Hz), 7.11 (1H, s),7.17-7.25 (4H, m), 7.69 (1H, s).

Example 205

By the reaction and treatment in the same manner as in Example 132 using5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.63 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as startingmaterials,5-benzyloxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.64 g) was obtained. By the reaction and treatment in the same manneras in Example 133 using this compound (0.50 g),5-hydroxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained.

Example 206

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57 g) and(4-bromophenyl)[(4-dimethylaminophenyl)methyl]amide (0.61 g) as startingmaterials,5-benzyloxy-N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.14 g) was obtained. By the reaction and treatment in the same manneras in Example 133 using this compound,N-(4-bromophenyl)-N-[(dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g) was obtained. melting point: 218-220° C.

Example 207

To a solution of 2-tolualdehyde (120 mg) in 1,2-dichloroethane (5 mL)were added 4-isopropylaniline (171 μL), acetic acid (57.2 μL) and sodiumtriacetoxyborohydride (445 mg), and the mixture was stirred for one day.Saturated aqueous sodium hydrogencarbonate (2 mL) was added to thereaction solution, and the mixture was applied to ExtruteNT-3 (Merck)column and eluted with ethyl acetate (10 mL) 10 min later. The obtainedsolution was treated with Sep-Pak Plus Silica (Waters), and the obtainedsolution was concentrated under reduced pressure. The obtained residuewas dissolved in methylene chloride (5 mL), and 4-dimethylaminopyridine(30 mg), 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (250mg) and N-cyclohexylcarbodiimide-N′-methylpolystyrene HL (1.5 g) wereadded. The mixture was stirred for one day, and the reaction mixture wasfiltrated under reduced pressure. The solvent was evaporated underreduced pressure, and THF (5 mL) and Ambersep 900 OH (800 mg) wereadded. The mixture was stirred for 3 hr. The reaction mixture wasfiltrated under reduced pressure. Amberlyst 15 (1 g) was added, and themixture was stirred for one day. The reaction mixture was filtratedunder reduced pressure, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto giveN-(4-isopropylphenyl)-7-methoxy-N-(2-tolylethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(106 mg).

MS (ESI) m/z: 428 [MH]⁺

Example 208

By the reaction and treatment in the same manner as in Example 207 using1-naphthaldehyde (156 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(1-naphthyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(258.9 mg) was obtained.

MS (ESI) m/z: 464 [MH]⁺

Example 209

By the reaction and treatment in the same manner as in Example 207 using2,4-dichlorobenzaldehyde (175 mg) as a starting material instead of2-tolualdehyde,N-[(2,4-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(258.8 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 210

By the reaction and treatment in the same manner as in Example 207 using4-nitrobenzaldehyde (151 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(218.9 mg) was obtained.

MS (ESI) m/z: 459 [MH]⁺

Example 211

By the reaction and treatment in the same manner as in Example 207 using3-tolualdehyde (120 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-(3-tolylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(145.4 mg) was obtained. MS (ESI) m/z: 428 [MH]⁺

Example 212

By the reaction and treatment in the same manner as in Example 207 using4-tolualdehyde (120 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-(4-tolylmethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(116.4 mg) was obtained.

MS (ESI) m/z: 428 [MH]⁺

Example 213

By the reaction and treatment in the same manner as in Example 207 using2-fluorobenzaldehyde (124 mg) as a starting material instead of2-tolualdehyde,N-[(2-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(148 mg) was obtained.

MS (ESI) m/z: 432 [MH]⁺

Example 214

By the reaction and treatment in the same manner as in Example 207 using3-fluorobenzaldehyde (124 mg) as a starting material instead of2-tolualdehyde,N-[(3-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(190.9 mg) was obtained.

MS (ESI) m/z: 432 [MH]⁺

Example 215

By the reaction and treatment in the same manner as in Example 207 using4-fluorobenzaldehyde (124 mg) as a starting material instead of2-tolualdehyde,N-[(4-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(184.2 mg) was obtained.

MS (ESI) m/z: 432 [MH]⁺

Example 216

By the reaction and treatment in the same manner as in Example 207 using3-cyanobenzaldehyde (131 mg) as a starting material instead of2-tolualdehyde,N-[(3-cyanophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(191 mg) was obtained.

MS (ESI) m/z: 439 [MH]⁺

Example 217

By the reaction and treatment in the same manner as in Example 207 using2,4-dimethylbenzaldehyde (134 mg) as a starting material instead of2-tolualdehyde,N-[(2,4-dimethylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(119.4 mg) was obtained.

MS (ESI) m/z: 442 [MH]⁺

Example 218

By the reaction and treatment in the same manner as in Example 207 using2,5-dimethylbenzaldehyde (134 mg) as a starting material instead of2-tolualdehyde,N-[(2,5-dimethylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(123.3 mg) was obtained.

MS (ESI) m/z: 442 [MH]⁺

Example 219

By the reaction and treatment in the same manner as in Example 207 using2-methoxybenzaldehyde (136 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(2-methoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(190.9 mg) was obtained.

MS (ESI) m/z: 444 [MH]⁺

Example 220

By the reaction and treatment in the same manner as in Example 207 using3-methoxybenzaldehyde (136 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-N-[(3-methoxyphenyl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(173.1 mg) was obtained.

MS (ESI) m/z: 444 [MH]⁺

Example 221

By the reaction and treatment in the same manner as in Example 207 using2-chlorobenzaldehyde (141 mg) as a starting material instead of2-tolualdehyde,N-[(2-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(117.5 mg) was obtained.

MS (ESI) m/z: 448 [MH]⁺

Example 222

By the reaction and treatment in the same manner as in Example 207 using3-chlorobenzaldehyde (141 mg) as a starting material instead of2-tolualdehyde,N-[(3-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(197.6 mg) was obtained.

MS (ESI) m/z: 448 [MH]⁺

Example 223

By the reaction and treatment in the same manner as in Example 207 using2,3-difluorobenzaldehyde (142 mg) as a starting material instead of2-tolualdehyde,N-[(2,3-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(130.2 mg) was obtained.

MS (ESI) m/z: 450 [MH]⁺

Example 224

By the reaction and treatment in the same manner as in Example 207 using2,4-difluorobenzaldehyde (142 mg) as a starting material instead of2-tolualdehyde,N-[(2,4-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(179.1 mg) was obtained.

MS (ESI) m/z: 450 [MH]⁺

Example 225

By the reaction and treatment in the same manner as in Example 207 using2,5-difluorobenzaldehyde (142 mg) as a starting material instead of2-tolualdehyde,N-[(2,5-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(212.6 mg) was obtained.

MS (ESI) m/z: 450[M]⁺

Example 226

By the reaction and treatment in the same manner as in Example 207 using2,6-difluorobenzaldehyde (142 mg) as a starting material instead of2-tolualdehyde,N-[(2,6-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(87.8 mg) was obtained.

MS (ESI) m/z: 450 [MH]⁺

Example 227

By the reaction and treatment in the same manner as in Example 207 using3,4-difluorobenzaldehyde (142 mg) as a starting material instead of2-tolualdehyde,N-[(3,4-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(126.6 mg) was obtained.

MS (ESI) m/z: 450 [MH]⁺

Example 228

By the reaction and treatment in the same manner as in Example 207 using3,5-difluorobenzaldehyde (142 mg) as a starting material instead of2-tolualdehyde,N-[(3,5-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(151 mg) was obtained.

MS (ESI) m/z: 450 [MH]⁺

Example 229

By the reaction and treatment in the same manner as in Example 207 using2,3-methylenedioxybenzaldehyde (150 mg) as a starting material insteadof 2-tolualdehyde,N-[(1,3-dioxaindan-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(184.4 mg) was obtained.

MS (ESI) m/z: 458 [MH]⁺

Example 230

By the reaction and treatment in the same manner as in Example 207 using4-ethoxybenzaldehyde (150 mg) as a starting material instead of2-tolualdehyde,N-[(4-ethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(177.4 mg) was obtained.

MS (ESI) m/z: 458 [MH]⁺

Example 231

By the reaction and treatment in the same manner as in Example 207 using3,4-ethylenedioxybenzaldehyde (164 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(4-oxachroman-6-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(167.6 mg) was obtained.

MS (ESI) m/z: 472 [NH]⁺

Example 232

By the reaction and treatment in the same manner as in Example 207 using4-propoxybenzaldehyde (164 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(4-propoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(172.6 mg) was obtained.

MS (ESI) m/z: 472 [MH]⁺

Example 233

By the reaction and treatment in the same manner as in Example 207 using3,5-dimethoxybenzaldehyde (166 mg) as a starting material instead of2-tolualdehyde,N-[(3,5-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(199.9 mg) was obtained.

MS (ESI) m/z: 474 [MH]⁺

Example 234

By the reaction and treatment in the same manner as in Example 207 using2,3-dimethoxybenzaldehyde (166 mg) as a starting material instead of2-tolualdehyde,N-[(2,3-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(332 mg) was obtained.

MS (ESI) m/z: 474 [MH]⁺

Example 235

By the reaction and treatment in the same manner as in Example 207 using2,4-dimethoxybenzaldehyde (166 mg) as a starting material instead of2-tolualdehyde,N-[(2,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(69.3 mg) was obtained.

MS (ESI) m/z: 474 [MH]⁺

Example 236

By the reaction and treatment in the same manner as in Example 207 using2,5-dimethoxybenzaldehyde (166 mg) as a starting material instead of2-tolualdehyde,N-[(2,5-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(122.5 mg) was obtained.

MS (ESI) m/z: 474 [NH]⁺

Example 237

By the reaction and treatment in the same manner as in Example 207 using2,6-dimethoxybenzaldehyde (166 mg) as a starting material instead of2-tolualdehyde,N-[(2,6-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(248.9 mg) was obtained.

MS (ESI) m/z: 474 [MH]⁺

Example 238

By the reaction and treatment in the same manner as in Example 207 using3,4-dimethoxybenzaldehyde (166 mg) as a starting material instead of2-tolualdehyde,N-[(3,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(96.1 mg) was obtained.

MS (ESI) m/z: 474 [NH]⁺

Example 239

By the reaction and treatment in the same manner as in Example 207 using2-trifluoromethylbenzaldehyde (174 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(2-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(179.1 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 240

By the reaction and treatment in the same manner as in Example 207 using3-trifluoromethylbenzaldehyde (174 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(3-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(186.2 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 241

By the reaction and treatment in the same manner as in Example 207 using4-trifluoromethylbenzaldehyde (174 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(4-trifluoromethylphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(207.9 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 242

By the reaction and treatment in the same manner as in Example 207 using2,3-dichlorobenzaldehyde (175 mg) as a starting material instead of2-tolualdehyde,N-[(2,3-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(302.3 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 243

By the reaction and treatment in the same manner as in Example 207 using2,6-dichlorobenzaldehyde (175 mg) as a starting material instead of2-tolualdehyde,N-[(2,6-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(93.1 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 244

By the reaction and treatment in the same manner as in Example 207 using3,4-dichlorobenzaldehyde (175 mg) as a starting material instead of2-tolualdehyde,N-[(3,4-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(288.2 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 245

By the reaction and treatment in the same manner as in Example 207 using3,5-dichlorobenzaldehyde (175 mg) as a starting material instead of2-tolualdehyde,N-[(3,5-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(304.4 mg) was obtained.

MS (ESI) m/z: 482 [MH]⁺

Example 246

By the reaction and treatment in the same manner as in Example 207 using2-bromobenzaldehyde (185 mg) as a starting material instead of2-tolualdehyde,N-[(2-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(157.6 mg) was obtained.

MS (ESI) m/z: 492 [MH]⁺

Example 247

By the reaction and treatment in the same manner as in Example 207 using3-bromobenzaldehyde (185 mg) as a starting material instead of2-tolualdehyde,N-[(3-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(214.4 mg) was obtained.

MS (ESI) m/z: 492 [MH]⁺

Example 248

By the reaction and treatment in the same manner as in Example 207 using2,3,4-trimethoxybenzaldehyde (196 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,4-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(365.1 mg) was obtained.

MS (ESI) m/z: 504 [MH]⁺

Example 249

By the reaction and treatment in the same manner as in Example 207 using3,4,5-trimethoxybenzaldehyde (196 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(139.3 mg) was obtained.

MS (ESI) m/z: 504 [MH]⁺

Example 250

By the reaction and treatment in the same manner as in Example 207 using3-phenoxybenzaldehyde (198 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(3-phenoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(153.8 mg) was obtained.

MS (ESI) m/z: 506 [MH]⁺

Example 251

By the reaction and treatment in the same manner as in Example 207 using4-phenoxybenzaldehyde (198 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(4-phenoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(188.1 mg) was obtained.

MS (ESI) m/z: 506 [MH]⁺

Example 252

By the reaction and treatment in the same manner as in Example 207 using2,3,5-trichlorobenzaldehyde (209 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,5-trichlorophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(400.7 mg) was obtained.

MS (ESI) m/z: 516 [MH]⁺

Example 253

By the reaction and treatment in the same manner as in Example 207 using2,3,6-trichlorobenzaldehyde (209 mg) as a starting material instead of2-tolualdehyde,N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,6-trichlorophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(112.7 mg) was obtained.

MS (ESI) m/z: 516 [MH]⁺

Example 254

By the reaction and treatment in the same manner as in Example 82 using5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(5.94 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (2.95 g)as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(3.00 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=7.0 Hz), 1.44-1.50 (1H, m), 1.82-2.05(3H, m), 2.69-2.74 (2H, m), 2.87-2.94 (1H, m), 3.70-3.75 (1H, m), 4.69(1H, d, J=14.4 Hz), 4.86 (1H, d, J=14.4 Hz), 6.58 (1H, d, J=7.8 Hz),6.70 (1H, d, J=7.8 Hz), 7.01-7.07 (3H, m), 7.21-7.42 (7H, m), 7.51 (2H,s).

Example 255

By the reaction and treatment in the same manner as in Example 83 usingN-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.32 g) and methyl bromoacetate (0.31 mL) as starting materials, methyl2-(4-{[N-(4-isopropylphenyl)-N-(7-methoxy-1,2,3,4-tetrahydronaphthalene-1-yl)carbonyl)amino]methyl}pyrazol-1-yl)acetate(0.35 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.37-1.53 (1H, m), 1.78-2.07(3H, m), 2.52-2.62 (1H, m), 2.68-2.85 (1H, m), 2.92 (1H, sept, J=6.9Hz), 3.64-3.73 (1H, m), 3.69 (3H, s), 3.77 (3H, s), 4.60. (1H, d, J=13.9Hz), 4.87 (1H, d, J=13.9 Hz), 4.88 (2H, s), 6.45 (1H, d, J=2.4 Hz), 6.66(1H, dd, J=2.4, 8.4 Hz), 6.95 (1H, d, J=8.4 Hz), 7.06 (2H, d, J=8.4 Hz),7.23 (2H, d, J=8.4 Hz), 7.42 (1H, s), 7.49 (1H, s).

Example 256

Methyl2-(4-{[N-(4-isopropylphenyl)-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)amino]methyl}pyrazol-1-yl)acetate(0.34 g) was dissolved in a mixed solvent (10 mL) of ethanol:THF (2:1),and sodium borohydride (0.11 g) and lithium chloride (0.12 g) were addedthereto. The mixture was stirred at 50° C. for 3 hr. The reactionmixture was concentrated under reduced pressure and partitioned betweenwater and ethyl acetate. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated, and the residue was purified by silica gel columnchromatography to giveN-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.28-1.45 (1H, m), 1.77-1.99(3H, m), 2.47-2.71 (2H, m), 2.91 (1H, sept, J=6.9 Hz), 3.52-3.62 (1H,m), 3.64 (3H, s), 3.68 (2H, t, J=5.6 Hz), 4.08 (2H, t, J=5.6 Hz), 4.57(1H, d, J=13.9 Hz), 4.76 (1H, d, J=13.9 Hz), 6.40 (1H, d, J=2.4 Hz),6.69 (1H, dd, J=2.4, 8.4 Hz), 6.94 (1H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4Hz), 7.25 (1H, s), 7.33 (2H, d, J=8.4 Hz), 7.52 (1H, s).

Example 257

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.00 g) and ethyl bromoacetate (0.40 mL) as starting materials, ethyl2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-1-yloxy)acetate(1.09 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.28 (3H, t, J=7.1 Hz), 1.45(3H, t, J=7.1 Hz), 1.39-1.56 (1H, m), 1.78-2.06 (3H, m), 2.61-2.85 (2H,m), 2.92 (1H, sept, J=6.9 Hz), 3.64-3.74 (1H, m), 4.12 (2H, q, J=7.1Hz), 4.18 (2H, q, J=7.1 Hz), 4.56 (2H, s), 4.59 (1H, d, J=13.9 Hz), 4.83(1H, d, J=13.9 Hz), 6.53 (1H, d, J=8.1 Hz), 6.59 (1H, d, J=8.1 Hz), 7.01(1H, t, J=8.1 Hz), 7.05 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.33(1H, s), 7.41 (1H, s).

Example 258

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.00 g) as a starting material, ethyl2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-2-yloxy)acetate(1.11 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.30 (3H, t, J=7.1 Hz), 1.45(3H, t, J=7.1 Hz), 1.39-1.57 (1H, m), 1.79-2.02 (3H, m), 2.52-2.67 (1H,m), 2.74-2.89 (1H, m), 2.92 (1H, sept, J=6.9 Hz), 3.59-3.69 (1H, m),4.12 (2H, q, J=7.1 Hz), 4.25 (2H, q, J=7.1 Hz), 4.54 (2H, s), 4.59 (1H,d, J=13.9 Hz), 4.81 (1H, d, J=13.9 Hz), 6.58 (1H, d, J=2.4 Hz), 6.65(1H, dd, J=2.4, 8.4 Hz), 6.82 (1H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4 Hz),7.22 (2H, d, J=8.4 Hz), 7.33 (1H, s), 7.40 (1H, s).

Example 259

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.00 g) as a starting material, ethyl2-(8-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-2-yloxy)acetate(0.94 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.31 (3H, t, J=7.1 Hz), 1.45(3H, t, J=7.1 Hz), 1.37-1.55 (1H, m), 1.78-2.05 (3H, m), 2.51-2.65 (1H,m), 2.70-2.84 (1H, m), 2.92 (1H, sept, J=6.9 Hz), 3.61-3.72 (1H, m),4.14 (2H, q, J=7.1 Hz), 4.27 (2H, q, J=7.1 Hz), 4.51 (2H, s), 4.65 (1H,d, J=13.9 Hz), 4.76 (1H, d, J=13.9 Hz), 6.50 (1H, d, J=2.4 Hz), 6.65(1H, dd, J=2.4, 8.4 Hz), 6.95 (1H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz),7.23 (2H, d, J=8.4 Hz), 7.31 (1H, s), 7.42 (1H, s).

Example 260

By the reaction and treatment in the same manner as in Example 12 using4-methoxyindan-1-carboxylic acid (0.29 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-carboxamide(0.39 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.31 (3H, t, J=7.1 Hz),2.01-2.17 (1H, m), 2.24-2.39 (1H, m), 2.60-2.75 (1H, m), 2.92 (1H, sept,J=6.9 Hz), 3.00-3.12 (1H, m), 3.79 (3H, s), 3.96 (1H, t, J=6.2 Hz), 4.12(2H, q, J=7.1 Hz), 4.65 (1H, d, J=13.9 Hz), 4.79 (1H, d, J=13.9 Hz),6.66 (2H, d, J=8.4 Hz), 6.99-7.16 (3H, m), 7.23 (2H, d, J=8.4 Hz), 7.31(1H, s), 7.39 (1H, s).

Example 261

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) asstarting materials,5-[2-(dimethylamino)ethyloxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.15 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.1 Hz),1.39-1.53 (1H, m), 1.71-2.07 (3H, m), 2.35 (6H, s), 2.56-2.69 (2H, m),2.75 (2H, t, J=5.8 Hz), 2.92 (1H, sept, J=6.9 Hz), 3.66-3.75 (1H, m),4.04 (2H, t, J=5.8 Hz), 4.12 (2H, q, J=7.1 Hz), 4.58 (1H, d, J=13.9 Hz),4.83 (1H, d, J=13.9 Hz), 6.54 (1H, d, J=8.1 Hz), 6.64 (1H, d, J=8.1 Hz),6.98-7.10 (3H, m), 7.22 (2H, d, J=8.4 Hz), 7.33 (1H, s), 7.41 (1H, s).

Example 262

By the reaction and treatment in the same manner as in Example 256 usingethyl2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-2-yloxy)acetate(0.56 g) as a starting material,N-[(1-ethylpyrazol-4-yl)methyl]-6-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.46 g) was obtained. melting point: 137.3° C.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),1.40-1.55 (1H, m), 1.80-2.12 (3H, m), 2.53-2.68 (1H, m), 2.77-3.00 (2H,m), 3.59-3.69 (1H, m), 3.87-3.95 (2H, m), 3.97-4.05 (2H, m), 4.13 (2H,q, J=7.3 Hz), 4.60 (1H, d, J=13.9 Hz), 4.81 (1H, d, J=13.9 Hz), 6.60(1H, d, J=2.4 Hz), 6.65 (1H, dd, J=2.4, 8.4 Hz), 6.82 (1H, d, J=8.4 Hz),7.04 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 7.33 (1H, s), 7.40 (1H,s).

Example 263

By the reaction and treatment in the same manner as in Example 256 usingethyl2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-1-yloxy)acetate(0.60 g) as starting materials,N-[(1-ethylpyrazol-4-yl)methyl]-5-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.46 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.1 Hz),1.39-1.55 (1H, m), 1.77-2.19 (3H, m), 2.60-2.72 (2H, m), 2.92 (1H, sept,J=6.9 Hz), 3.66-3.73 (1H, m), 3.87-3.96 (2H, m), 4.03 (2H, t, J=4.3 Hz),4.13 (2H, q, J=7.1 Hz), 4.59 (1H, d, J=13.9 Hz), 4.83 (1H, d, J=13.9Hz), 6.57 (1H, d, J=8.1 Hz), 6.65 (1H, d, J=8.1 Hz), 6.97-7.10 (3H, m),7.22 (2H, d, J=8.4 Hz), 7.33 (1H, s), 7.40 (1H, s).

Example 264

By the reaction and treatment in the same manner as in Example 256 usingethyl2-(8-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-2-yloxy)acetate(0.47 g) as starting materials,N-[(1-ethylpyrazol-4-yl)methyl]-7-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.40 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.1 Hz),1.39-1.55 (1H, m), 1.69-2.05 (3H, m), 2.51-2.84 (3H, m), 2.93 (1H, sept,J=6.9 Hz), 3.63-3.72 (1H, m), 3.82-3.98 (4H, m), 4.13 (2H, q, J=7.1 Hz),4.43 (1H, d, J=13.9 Hz), 4.99 (1H, d, J=13.9 Hz), 6.41 (1H, d, J=2.4Hz), 6.66 (1H, dd, J=2.4, 8.4 Hz), 6.94 (1H, d, J=8.4 Hz), 7.08 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.44 (2H, s).

Example 265

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) asstarting materials,6-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.19 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.43 (3H, t, J=7.1 Hz),1.40-1.53 (1H, m), 1.69-2.04 (3H, m), 2.31 (6H, s), 2.52-2.67 (1H, m),2.69 (2H, t, J=5.8 Hz), 2.73-2.90 (1H, m), 2.92 (1H, sept, J=6.9 Hz),3.60-3.70 (1H, m), 4.00 (2H, t, J=5.8 Hz), 4.12 (2H, q, J=7.1 Hz), 4.58(1H, d, J=13.9 Hz), 4.82 (1H, d, J=13.9 Hz), 6.59 (1H, d, J=2.4 Hz),6.66 (1H, dd, J=2.4, 8.4 Hz), 6.80 (1H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4Hz), 7.22 (2H, d, J=8.4 Hz), 7.32 (1H, s), 7.40 (1H, s).

Example 266

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) asstarting materials,7-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.15 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.43 (3H, t, J=7.1 Hz),1.39-1.56 (1H, m), 1.77-2.07 (3H, m), 2.33 (6H, s), 2.50-2.83 (4H, m),2.92 (1H, sept, J=6.9 Hz), 3.63-3.73 (1H, m), 3.94 (2H, t, J=5.8 Hz),4.13 (2H, q, J=7.1 Hz), 4.63 (1H, d, J=13.9 Hz), 4.78 (1H, d, J=13.9Hz), 6.48 (1H, d, J=2.4 Hz), 6.68 (1H, dd, J=2.4, 8.4 Hz), 6.94 (1H, d,J=8.4 Hz), 7.06 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 7.32 (1H, s),7.41 (1H, s).

Example 267

By the reaction and treatment in the same manner as in Example 106 usingN-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.24 g) asstarting materials,5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidewas obtained. This was dissolved in ethyl acetate, and oxalic acid (0.12g) was added. The precipitated solid was collected by filtration to give5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide3/2 oxalate (0.36 g). melting point: 142.6° C.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.44 (3H, t, J=7.1 Hz),1.36-1.57 (1H, m), 1.72-2.07 (3H, m), 2.14-2.31 (2H, m), 2.52-2.67 (2H,m), 2.88 (6H, s), 2.92 (1H, sept, J=6.9 Hz), 3.20-3.47 (2H, m),3.67-3.78 (1H, m), 3.92-4.08 (2H, m), 4.14 (2H, q, J=7.1 Hz), 4.58 (1H,d, J=13.9 Hz), 4.80 (1H, d, J=13.9 Hz), 6.53 (1H, d, J=8.1 Hz), 6.59(1H, d, J=8.1 Hz), 6.96-7.10 (3H, m), 7.24 (2H, d, J=8.4 Hz), 7.36 (1H,s), 7.40 (1H, s).

Example 268

By the reaction and treatment in the same manner as in Example 106 usingN-[1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.46 g) and 1,4-dibromobutane (1.33 mL) as starting materials,5-(4-bromobutoxy)-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.38-1.51 (1H, m), 1.45 (3H,t, J=7.1 Hz), 1.66-2.10 (7H, m), 2.57-2.69 (2H, m), 2.92 (1H, sept,J=6.9 Hz), 3.48 (2H, t, J=5.8 Hz), 3.65-3.75 (1H, m), 3.94 (2H, t, J=5.8Hz), 4.13 (2H, q, J=7.1 Hz), 4.58 (1H, d, J=13.9 Hz), 4.84 (1H, d,J=13.9 Hz), 6.54 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=8.4 Hz), 6.96-7.09(3H, m), 7.22 (2H, d, J=8.4 Hz), 7.33 (1H, s), 7.41 (1H, s).

Example 269

To a solution of5-(4-bromobutoxy)-N-[(l-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) in acetonitrile (10 mL) were added dimethylamine hydrochloride(0.69 g) and potassium carbonate (1.30 g), and the mixture was heatedunder reflux for 1.5 hr. The reaction mixture was concentrated underreduced pressure, and the residue was partitioned between water andchloroform. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography to give5-[4-(dimethylamino)butoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.27 g).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.45 (3H,t, J=7.1 Hz), 1.64-2.07 (7H, m), 2.31 (6H, s), 2.39-2.71 (4H, m), 2.92(1H, sept, J=6.9 Hz), 3.65-3.76 (1H, m), 3.92 (2H, t, J=5.8 Hz), 4.12(2H, q, J=7.1 Hz), 4.58 (1H, d, J=13.9 Hz), 4.83 (1H, d, J=13.9 Hz),6.53 (1H, d, J=8.0 Hz), 6.62 (1H, d, J=8.0 Hz), 6.96-7.10 (3H, m), 7.22(2H, d, J=8.4 Hz), 7.33 (1H, s), 7.41 (1H, s).

Example 270

By the reaction and treatment in the same manner as in Example 12 using1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.35 g) and(4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.58 g) asstarting materials,N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.9 Hz), 1.41-1.60 (1H, m), 1.83-2.09(3H, m), 2.59-2.72 (1H, m), 2.79-3.00 (2H, m), 3.70-3.81 (1H, m), 4.72(1H, d, J=14.4 Hz), 4.89 (1H, d, J=14.4 Hz), 6.90-6.99 (1H, m),7.00-7.17 (5H, m), 7.21-7.31 (3H, m), 7.37-7.47 (2H, m), 7.58 (1H, s),7.66 (2H, d, J=9.0 Hz), 7.94 (1H, s).

Example 271

To a solution of5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.27 g) in methylene chloride (2 mL) were added tetra-n-butylammoniumhydrogensulfate (0.66 g), 2-(chloromethyl)pyridine hydrochloride (0.19g) and 1 mol/L-aqueous sodium hydroxide solution (2.26 mL), and themixture was stirred at room temperature for one day. The reactionmixture was partitioned between water and chloroform. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.19 g).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.38-1.56 (1H, m), 1.78-2.07(3H, m), 2.61-2.82 (2H, m), 2.91 (1H, sept, J=6.9 Hz), 3.67-3.77 (1H,m), 4.64 (1H, d, J=14.4 Hz), 4.86 (1H, d, J=14.4 Hz), 5.01 (2H, s), 5.40(2H, s), 6.59 (1H, d, J=7.7 Hz), 6.69 (1H, d, J=8.2 Hz), 6.87-7.08 (4H,m), 7.15-7.49 (10H, m), 7.57-7.66 (1H, m), 8.56 (1H, d, J=5.7 Hz).

Example 272

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.19 g) as a starting material,5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.08 g) was obtained. MS (ESI) m/z: 481 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.19 (6H, d, J=6.9 Hz), 1.27-1.42 (1H, m), 1.70-2.00(3H, m), 2.37-2.57 (2H, m), 2.91 (1H, sept, J=6.9 Hz), 3.50-3.60 (1H,m), 4.66 (1H, d, J=14.7 Hz), 4.73 (1H, d, J=14.7 Hz), 5.56 (2H, s), 6.41(1H, d, J=7.5 Hz), 6.60 (1H, d, J=7.8 Hz), 6.85 (1H, t, J=7.8 Hz),7.10-7.22 (3H, m), 7.27-7.37 (3H, m), 7.59-7.68 (1H, m), 7.74 (1H, s),8.14 (1H, m), 8.73 (1H, d, J=4.5 Hz).

Example 273

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.36 g) and benzyl bromide (0.18 mL) as startingmaterials,5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.34 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.54 (1H, m), 1.76-2.06(3H, m), 2.61-2.78 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.58-3.68 (1H,m), 4.60 (1H, d, J=14.7 Hz), 4.84 (1H, d, J=14.7 Hz), 5.01 (2H, s), 5.24(2H, s), 6.52 (1H, d, J=7.8 Hz), 6.70 (1H, d, J=8.1 Hz), 6.98 (1H, t,J=8.0 Hz), 7.11-7.18 (3H, m), 7.22-7.43 (11H, m), 8.38 (1H, d, J=2.4Hz).

Example 274

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-5-carboxamide(0.34 g) as starting materials,N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.27 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.37-1.55 (1H, m), 1.72-1.95(3H, m), 2.37-2.58 (3H, m), 3.23-3.39 (1H, m), 4.63-4.90 (2H, m), 5.27(2H, s), 6.46 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=7.8 Hz), 6.87 (1H, t,J=7.8 Hz), 7.05-7.15 (2H, m), 7.23-7.38 (4H, m), 7.60-7.88 (2H, m),8.03-8.18 (1H, m), 8.69-8.82 (1H, m).

Example 275

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-(chloromethyl)pyridine hydrochloride (0.49g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.74 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.78-2.07(3H, m), 2.61-2.82 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.58-3.67 (1H,m), 4.66 (1H, d, J=14.4 Hz), 4.86 (1H, d, J=14.7 Hz), 5.03 (2H, s), 5.41(2H, s), 6.54 (H, d, J=7.8 Hz), 6.71 (1H, d, J=8.1 Hz), 6.90-7.03 (2H,m), 7.15-7.50 (10H, m), 7.58-7.67 (1H, m), 8.39 (1H, d, J=2.4 Hz), 8.57(1H, dd, J=(0.6, 4.8 Hz).

Example 276

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-(2-pyridylmethyl)pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.72 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.56 g) was obtained.

MS (ESI) m/z: 482 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.37-1.55 (1H, m), 1.70-1.95(3H, m), 2.34-2.58 (2H, m), 3.24-3.65 (2H, m), 4.50-5.05 (2H, m), 5.62(2H, s), 6.49 (1H, d, J=7.7 Hz), 6.54 (1H, d, J=7.9 Hz), 6.87 (1H, t,J=7.8 Hz), 7.23 (1H, d, J=7.9 Hz), 7.31-7.43 (1H, m), 7.63-7.90 (3H, m),8.05-8.29 (2H, m), 8.63-0.79 (2H, m).

Example 277

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 3-(chloromethyl)pyridine hydrochloride (0.49g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.68 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.38-1.55 (1H, m), 1.75-2.07(3H, m), 2.60-2.82 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 4.61 (1H, d, J=14.5 Hz), 4.84 (1H, d, J=14.5 Hz), 5.03 (2H, s), 5.28(2H, s), 6.49 (1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1 Hz), 7.00 (1H, t,J=7.9 Hz), 7.18 (1H, d, J=8.3 Hz), 7.23-7.51 (10H, m), 8.38 (1H, d,J=2.4 Hz), 8.50 (1H, d, J=2.0 Hz), 8.57 (1H, dd, J=1.6, 4.8 Hz).

Example 278

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.51 g) was obtained.

MS (ESI) m/z: 482 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.33-1.53 (1H, m), 1.69-1.93(3H, m), 2.36-2.61 (2H, m), 3.20-3.64 (2H, m), 4.60-4.96 (2H, m), 5.55(2H, s), 6.47 (1H, d, J=7.6 Hz), 6.65 (1H, d, J=7.8 Hz), 6.87 (1H, t,J=7.8 Hz), 7.30-7.44 (1H, m), 7.68-7.92 (2H, m), 7.98-8.16 (2H, m), 8.27(1H, d, J=8.1 Hz), 8.61-0.82 (2H, m), 8.88 (1H, d, J=5.1 Hz).

Example 279

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-fluorobenzyl chloride (0.36 mL) as startingmaterials,5-benzyloxy-N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.37-1.53 (1H, m), 1.77-2.07(3H, m), 2.60-2.81 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.57-3.66 (1H,m), 4.60 (1H, d, J=14.5 Hz), 4.84 (1H, d, J=14.5 Hz), 5.03 (2H, s), 5.22(2H, s), 6.49 (1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1 Hz), 6.92-7.05 (3H,m), 7.11-7.20 (3H, m), 7.24-7.44 (8H, m), 8.36 (1H, d, J=2.4 Hz).

Example 280

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.59 g) was obtained.

MS (ESI) m/z: 499 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.33-1.50 (1H, m), 1.68-1.94(3H, m), 2.34-2.60 (2H, m), 3.20-3.63 (2H, m), 4.60-4.87 (2H, m), 5.26(2H, s), 6.45 (1H, d, J=7.6 Hz), 6.63 (1H, d, J=7.8 Hz), 6.86 (1H, t,J=7.8 Hz), 7.07-7.22 (4H, m), 7.25-7.37 (1H, m), 7.57-7.78 (2H, m),7.92-8.10 (1H, m), 8.59-8.75 (1H, m).

Example 281

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-chlorobenzyl chloride (0.48 g) as startingmaterials,5-benzyloxy-N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.37-1.57 (1H, m), 1.77-2.07(3H, m), 2.60-2.82 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 4.59 (1H, d, J=14.5 Hz), 4.84 (1H, d, J=14.5 Hz), 5.03 (2H, s), 5.22(2H, s), 6.49 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=8.1 Hz), 6.97 (1H, t,J=7.9 Hz), 7.11 (2H, d, J=8.4 Hz), 7.17 (1H, d, J=8.3 Hz), 7.24-7.43(10H, m), 8.37 (1H, d, J=2.4 Hz).

Example 282

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.65 g) was obtained.

MS (ESI) m/z: 515 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.36-1.53 (1H, m), 1.67-1.95(3H, m), 2.33-2.57 (2H, m), 3.17-3.67 (2H, m), 4.59-4.89 (2H, m), 5.27(2H, s), 6.45 (1H, d, J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.86 (1H, t,J=7.8 Hz), 7.15 (2H, d, J=8.4 Hz), 7.22-7.36 (1H, m), 7.41 (2H, d, J=8.4Hz), 7.57-7.78 (2H, m), 7.90-8.08 (1H, m), 8.58-8.72 (1H, m).

Example 283

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-(trifluoromethyl)benzyl chloride (0.48 g)as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.84 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.37-1.57 (1H, m), 1.78-2.07(3H, m), 2.60-2.82 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.58-3.68 (1H,m), 4.61 (1H, d, J=14.5 Hz), 4.85 (1H, d, J=14.5 Hz), 5.03 (2H, s), 5.31(2H, s), 6.49 (1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1 Hz), 6.96 (1H, t,J=7.9 Hz), 7.18 (1H, d, J=8.3 Hz), 7.23-7.46 (10H, m), 7.60 (2H, d,J=8.2 Hz), 8.38 (1H, d, J=2.4 Hz).

Example 284

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.67 g) was obtained. MS (ESI) m/z: 549 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.27 (6H, d, J=6.9 Hz), 1.33-1.50 (1H, m), 1.70-1.96(3H, m), 2.34-2.59 (2H, m), 3.12-3.67 (2H, m), 4.64-4.87 (2H, m), 5.40(2H, s), 6.45 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.8 Hz), 6.84 (1H, t,J=7.7 Hz), 7.22-7.40 (3H, m), 7.57-7.77 (4H, m), 7.89-8.05 (1H, m),8.56-8.71 (1H, m).

Example 285

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 3-chloromethyl-6-isopropylpyridine (0.51 g)as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin-3-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 1.31 (6H, d, J=6.9 Hz),1.37-1.54 (1H, m), 1.77-2.07 (3H, m), 2.60-2.82 (2H, m), 2.99-3.17 (2H,m), 3.57-3.67 (1H, m), 4.61 (1H, d, J=14.7 Hz), 4.83 (1H, d, J=14.4 Hz),5.03 (2H, s), 5.24 (2H, s), 6.50 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=8.1Hz), 6.99 (1H, t, J=8.0 Hz), 7.10-7.19 (2H, m), 7.25-7.45 (9H, m), 8.38(1H, d, J=2.4 Hz), 8.42 (1H, d, J=2.1 Hz).

Example 286

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin-3-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin-3-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.57 g) was obtained. MS (ESI) m/z: 524 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.35 (6H, d, J=6.9 Hz),1.37-1.50 (1H, m), 1.70-1.97 (3H, m), 2.34-2.60 (2H, m), 3.23-3.62 (3H,m), 4.63-4.88 (2H, m), 5.52 (2H, s), 6.47 (1H, d, J=7.5 Hz), 6.64 (1H,d, J=8.1 Hz), 6.87 (1H, t, J=7.8 Hz), 7.30-7.45 (1H, m), 7.72-7.89 (2H,m), 7.96-8.16 (2H, m), 8.25 (1H, dd, J=1.8, 8.1 Hz), 8.58-8.78 (2H, m).

Example 287

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 5-(chloromethyl)-2,4-dimethylthiazole (0.49g) as starting materials,5-benzyloxy-N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.92 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.37-1.57 (1H, m), 1.77-2.09(3H, m), 2.34 (3H, s), 2.39 (3H, s), 2.67-2.83 (2H, m), 3.09 (1H, sept,J=6.9 Hz), 3.57-3.67 (1H, m), 4.59 (1H, d, J=14.4 Hz), 4.82 (1H, d,J=14.4 Hz), 5.03 (2H, s), 5.31 (2H, s), 6.50 (1H, d, J=7.5 Hz), 6.72(1H, d, J=8.1 Hz), 7.01 (1H, t, J=8.0 Hz), 7.18 (1H, d, J=8.4 Hz),7.24-7.42 (8H, m), 8.36 (1H, d, J=2.4 Hz).

Example 288

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.91 g) as a starting material,N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.35 g) was obtained.

MS (ESI) m/z: 516 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.34-1.50 (1H, m), 1.70-1.95(3H, m), 2.34 (3H, s), 2.37-2.57 (2H, m), 2.62 (3H, s), 3.17-3.67 (2H,m), 4.60-4.85 (2H, m), 5.43 (2H, s), 6.44 (1H, d, J=7.7 Hz), 6.63 (1H,d, J=7.9 Hz), 6.87 (1H, t, J=7.8 Hz), 7.25-7.39 (1H, m), 7.60-7.80 (2H,m), 7.92-8.07 (1H, m), 8.57-8.72 (1H, m).

Example 289

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-methoxybenzyl chloride (0.41 mL) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.37-1.53 (1H, m), 1.75-2.07(3H, m), 2.60-2.82 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 3.79 (3H, s), 4.59 (1H, d, J=14.4 Hz), 4.83 (1H, d, J=14.4 Hz), 5.03(2H, s), 5.19 (2H, s), 6.50 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=8.1 Hz),6.86 (2H, d, J=6.3 Hz), 6.99 (1H, t, J=8.1 Hz), 7.10-7.18 (3H, m),7.23-7.45 (8H, m), 8.37 (1H, d, J=2.4 Hz).

Example 290

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.54 g) was obtained.

MS (ESI) m/z: 511 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.27 (6H, d, J=6.9 Hz), 1.31-1.50 (1H, m), 1.70-1.96(3H, m), 2.35-2.60 (2H, m), 3.10-3.70 (2H, m), 3.73 (3H, s), 4.61-4.85(2H, m), 5.18 (2H, s), 6.43 (1H, d, J=7.57 Hz), 6.62 (1H, d, J=7.9 Hz),6.80-6.92 (3H, m), 7.11 (2H, d, J=8.4 Hz), 7.22-7.34 (1H, m), 7.51-7.68(2H, m), 7.83-7.97 (1H, m), 8.52-8.67 (1H, m).

Example 291

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-chloromethyl-1-ethylpyrazole (0.43 g) asstarting materials,5-benzyloxy-N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.46 (3H, t, J=7.2 Hz),1.38-1.55 (1H, m), 1.73-2.07 (3H, m), 2.60-2.80 (2H, m), 3.08 (1H, sept,J=6.9 Hz), 3.57-3.66 (1H, m), 4.14 (2H, q, J=7.2 Hz), 4.58 (2H, s), 4.65(1H, d, J=14.7 Hz), 4.78 (1H, d, J=14.4 Hz), 5.02 (2H, s), 6.16 (1H, s),6.52 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=5.1 Hz), 7.03 (1H, t, J=7.9 Hz),7.17 (1H, d, J=8.3 Hz), 7.23-7.56 (9H, m), 8.35 (1H, d, J=2.4 Hz).

Example 292

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) as a starting material,N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.34 g) was obtained. MS (ESI) m/z: 499 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.32 (3H, t, J=7.2 Hz),1.38-1.50 (1H, m), 1.70-1.96 (3H, m), 2.36-2.58 (2H, m), 3.08-3.50 (2H,m), 4.08 (2H, q, J=7.2 Hz), 4.58-4.81 (2H, m), 5.10 (2H, s), 6.43 (1H,d, J=7.5 Hz), 6.62 (1H, d, J=8.1 Hz), 6.87 (1H, t, J=7.7 Hz), 7.18-7.36(2H, m), 7.48-7.68 (3H, m), 7.82-7.97 (1H, m), 8.50-8.63 (1H, m).

Example 293

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.66 g) and methyl 4-(bromomethyl)benzoate (0.31 g) asstarting materials, methyl4-[(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate(0.61 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.37-1.54 (1H, m), 1.77-2.08(3H, m), 2.60-2.82 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.58-3.68 (1H,m), 3.91 (3H, s), 4.62 (1H, d, J=14.5 Hz), 4.85 (1H, d, J=14.5 Hz), 5.03(2H, s), 5.31 (2H, s), 6.50 (1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1 Hz),6.98 (1H, t, J=7.9 Hz), 7.14-7.46 (12H, m), 8.01 (1H, dd, J=1.7, 8.3Hz), 8.38 (1H, d, J=2.4 Hz).

Example 294

By the reaction and treatment in the same manner as in Example 101 usingmethyl4-[(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate(0.61 g) as a starting material, methyl4-[(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoatehydrochloride (0.51) was obtained.

MS (ESI) m/z: 539 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.35-1.50 (1H, m), 1.72-1.97(3H, m), 2.36-2.60 (2H, m), 3.15-3.70 (2H, m), 3.85 (3H, s), 4.65-4.90(2H, m), 5.38 (2H, s), 6.45 (1H, d, J=7.6 Hz), 6.62 (1H, d, J=7.8 Hz),6.85 (1H, t, J=7.8 Hz), 7.21 (2H, d, J=8.3 Hz), 7.29-7.42 (1H, m),7.58-7.75 (1H, m), 7.90-8.02 (4H, m), 8.58-8.71 (1H, m).

Example 295

Methyl4-[(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate(0.36 g) was dissolved in a mixed solvent (4 mL) of ethanol: 1mol/L-aqueous sodium hydroxide solution (1:1), and the mixture wasstirred at room temperature for one day. The reaction mixture wasconcentrated under reduced pressure, and the residue was partitionedbetween water and toluene. Citric acid was added to the aqueous layeruntil the mixture is acidified. The aqueous layer was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was dissolved in ethyl acetate. Thereto was added 4mol/L-HCl/dioxane. The precipitated solid was collected by filtration togive4-[(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoicacid hydrochloride (0.27 g).

MS (ESI) m/z: 525 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.26 (6H, d, J=6.9 Hz), 1.33-1.51 (1H, m), 1.70-1.98(3H, m), 2.34-2.60 (2H, m), 3.07-3.60 (2H, m), 4.65-4.89 (2H, m), 5.37(2H, s), 6.44 (1H, d, J=7.5 Hz), 6.61 (1H, d, J=7.8 Hz), 6.85 (1H, t,J=7.7 Hz), 7.18 (2H, d, J=7.9 Hz), 7.27-7.40 (1H, m), 7.52-7.73 (2H, m),7.80-7.97 (3H, m), 8.50-8.68 (1H, m).

Example 296

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-bromobenzyl chloride (0.75 g) as startingmaterials,5-benzyloxy-N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.38-1.54 (1H, m), 1.75-2.07(3H, m), 2.61-2.82 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 4.59 (1H, d, J=14.4 Hz), 4.84 (1H, d, J=14.7 Hz), 5.03 (2H, s), 5.20(2H, s), 6.48 (1H, d, J=7.5 Hz), 6.72 (1H, d, J=8.1 Hz), 6.97 (1H, t,J=7.8 Hz), 7.05 (2H, d, J=8.1 Hz), 7.17 (1H, d, J=8.1 Hz), 7.25-7.49(10H, m), 8.37 (1H, d, J=2.4 Hz).

Example 297

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.83 g) as a starting material,N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.68 g) was obtained.

MS (ESI) m/z: 559, 561 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.34-1.52 (1H, m), 1.69-1.95(3H, m), 2.34-2.58 (2H, m), 3.18-3.66 (2H, m), 4.62-4.90 (2H, m), 5.26(2H, s), 6.44 (1H, d, J=7.6 Hz), 6.63 (1H, d, J=7.8 Hz), 6.86 (1H, t,J=7.8 Hz), 7.08 (2H, d, J=8.4 Hz), 7.23-7.42 (1H, m), 7.54 (2H, d, J=8.3Hz), 7.59-7.79 (2H, m), 7.92-8.10 (1H, m), 8.60-8.79 (1H, m).

Example 298

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 3-chlorobenzyl chloride (0.38 mL) as startingmaterials,5-benzyloxy-N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.56 (1H, m), 1.87-2.07(3H, m), 2.62-2.83 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.58-3.68 (1H,m), 4.62 (1H, d, J=14.4 Hz), 4.84 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.23(2H, s), 6.51 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=8.1 Hz), 6.93-7.19 (3H,m), 7.24-7.47 (11H, m), 8.40 (1H, d, J=2.4 Hz).

Example 299

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) as a starting material,N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.62 g) was obtained.

MS (ESI) m/z: 515 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.34-1.54 (1H, m), 1.70-1.96(3H, m), 2.37-2.62 (2H, m), 3.21-3.70 (2H, m), 4.60-4.92 (2H, m), 5.30(2H, s), 6.46 (1H, d, J=7.6 Hz), 6.63 (1H, d, J=7.8 Hz), 6.86 (1H, t,J=7.8 Hz), 7.02-7.12 (1H, m), 7.20 (1H, s), 7.27-7.44 (3H, m), 7.62-7.82(2H, m), 7.93-8.12 (1H, m), 8.63-8.85 (1H, m).

Example 300

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-chlorobenzyl chloride (0.38 mL) as startingmaterials,5-benzyloxy-N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.55 (1H, m), 1.76-2.08(3H, m), 2.61-2.82 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 4.66 (1H, d, J=14.4 Hz), 4.84 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.38(2H, s), 6.53 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=8.1 Hz), 6.96-7.06 (2H,m), 7.13-7.45 (12H, m), 8.38 (1H, d, J=2.4 Hz).

Example 301

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.61 g) was obtained.

MS (ESI) m/z: 515 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.32-1.53 (1H, m), 1.70-1.98(3H, m), 2.36-2.61 (2H, m), 3.21-3.67 (2H, m), 4.64-4.90 (2H, m), 5.37(2H, s), 6.47 (1H, d, J=7.6 Hz), 6.64 (1H, d, J=7.9 Hz), 6.79-6.91 (2H,m), 7.23-7.50 (4H, m), 7.57-7.85 (2H, m), 7.93-8.17 (1H, m), 8.62-8.94(1H, m).

Example 302

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-methylbenzyl chloride (0.42 g) as startingmaterials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.53 (1H, m), 1.77-2.07(3H, m), 2.33 (3H, s), 2.62-2.80 (2H, m), 3.08 (1H, sept, J=6.9 Hz),3.57-3.64 (1H, m), 4.60 (1H, d, J=14.4 Hz), 4.84 (1H, d, J=14.7 Hz),5.03 (2H, s), 5.21 (2H, s), 6.50 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=8.1Hz), 6.99 (1H, t, J=8.0 Hz), 7.03-7.18 (5H, m), 7.24-7.42 (8H, m), 8.37(1H, d, J=2.4 Hz).

Example 303

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) as starting materials,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.55 g) was obtained.

MS (ESI) m/z: 495 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.35-1.52 (1H, m), 1.68-1.95(3H, m), 2.27 (3H, s), 2.34-2.58 (2H, m), 3.25-3.63 (2H, m), 4.65-4.91(2H, m), 5.21 (2H, s), 6.45 (1H, d, J=7.6 Hz), 6.64 (1H, d, J=7.8 Hz),6.86 (1H, t, J=7.8 Hz), 7.03 (2H, d, J=8.0 Hz), 7.14 (2H, d, J=7.9 Hz),7.25-7.40 (1H, m), 7.64-7.86 (2H, m), 7.99-8.17 (1H, m), 8.66-8.82 (1H,m).

Example 304

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-(chloromethyl)-5-methylpyridine (0.43 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.71 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.40-1.57 (1H, m), 1.74-2.09(3H, m), 2.32 (3H, s), 2.61-2.80 (2H, m), 3.08 (1H, sept, J=6.9 Hz),3.58-3.67 (1H, m), 4.65 (1H, d, J=14.5 Hz), 4.85 (1H, d, J=14.5 Hz),5.03 (2H, s), 5.36 (2H, s), 6.54 (1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1Hz), 6.89 (1H, d, J=8.0 Hz), 7.01 (1H, t, J=7.9 Hz), 7.17 (1H, d, J=8.3Hz), 7.24-7.49 (9H, m), 8.38 (2H, s).

Example 305

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.71 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.62 g) was obtained. MS (ESI) m/z: 496 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.33-1.55 (1H, m), 1.71-1.97(3H, m), 2.43 (3H, s), 2.36-2.59 (2H, m), 3.29-3.64 (2H, m), 4.62-4.91(2H, m), 5.67 (2H, s), 6.49 (1H, d, J=7.7 Hz), 6.65 (1H, d, J=7.9 Hz),6.88 (1H, t, J=7.8 Hz), 7.28-7.41 (2H, m), 7.72-7.96 (2H, m), 8.12-8.29(2H, m), 8.63-8.80 (2H, m).

Example 306

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 6-chloromethyl-3-methoxypyridine (0.47 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.63 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.41-1.57 (1H, m), 1.76-2.09(3H, m), 2.61-2.82 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.68-3.77 (1H,m), 3.84 (3H, s), 4.65 (1H, d, J=14.5 Hz), 4.84 (1H, d, J=14.5 Hz), 5.03(2H, s), 5.33 (2H, s), 6.54 (1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.1 Hz),6.95-7.05 (2H, m), 7.11-7.19 (2H, m), 7.25-7.47 (8H, m), 8.25 (1H, d,J=2.9 Hz), 8.37 (1H, d, J=2.4 Hz).

Example 307

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.61 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.46 g) was obtained. MS (ESI) m/z: 512 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.37-1.54 (1H, m), 1.71-1.95(3H, m), 2.36-2.60 (2H, m), 3.31-3.65 (2H, m), 3.89 (3H, s), 4.67-4.90(2H, m), 5.49 (2H, s), 6.49 (1H, d, J=7.6 Hz), 6.65 (1H, d, J=7.8 Hz),6.88 (1H, t, J=7.8 Hz), 7.24 (1H, d, J=8.8 Hz), 7.29-7.42 (1H, m),7.71-7.96 (3H, m), 8.13-8.29 (1H, m), 8.44 (1H, d, J=2.7 Hz), 8.70-8.84(1H, m).

Example 308

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-chloromethyl-6-methylpyridine (0.43 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.56 (1H, m), 1.77-2.10(3H, m), 2.55 (3H, s), 2.62-2.83 (2H, m), 3.08 (1H, sept, J=6.9 Hz),3.58-3.68 (1H, m), 4.66 (1H, d, J=1.4 Hz), 4.86 (1H, d, J=14.7 Hz), 5.03(2H, s), 5.37 (2H, s), 6.54 (1H, d, J=7.8 Hz), 6.64-6.75 (2H, m),6.94-7.08 (2H, m), 7.18 (1H, d, J=8.1 Hz), 7.25-7.55 (9H, m), 8.39 (1H,d, J=2.4 Hz).

Example 309

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.74 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.63 g) was obtained. MS (ESI) m/z: 496 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.32-1.53 (1H, m), 1.70-1.99(3H, m), 2.34-2.58 (2H, m), 2.72 (3H, s), 3.15-3.34 (1H, m), 3.45-3.62(1H, m), 4.72 (1H, d, J=15.6 Hz), 4.83 (1H, d, J=14.7 Hz), 5.68 (2H, s),6.48 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz), 6.88 (1H, t, J=7.8 Hz),7.07 (1H, d, J=8.1 Hz), 7.29-7.48 (1H, m), 7.61-8.32 (5H, m), 8.57-8.74(1H, m).

Example 310

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-(chloromethyl)-4-methylpyridine (0.53 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.75-2.08(3H, m), 2.31 (3H, s), 2.60-2.82 (2H, m), 3.08 (1H, sept, J=6.9 Hz),3.57-3.69 (1H, m), 4.67 (1H, d, J=14.4 Hz), 4.85 (1H, d, J=14.4 Hz),5.03 (2H, s), 5.36 (2H, s), 6.55 (1H, d, J=7.5 Hz), 6.72 (1H, d, J=7.8Hz), 6.80 (1H, s), 6.93-7.06 (2H, m), 7.13-7.50 (9H, m), 8.33-8.46 (2H,m).

Example 311

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.57 g) was obtained. MS (ESI) m/z: 496 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.35-1.51 (1H, m), 1.70-1.97(3H, m), 2.36-2.62 (5H, m), 3.19-3.39 (1H, m), 3.45-3.64 (1H, m), 4.71(1H, d, J=14.0 Hz), 4.85 (1H, d, J=14.1 Hz), 5.69 (2H, s), 6.49 (1H, d,J=7.7 Hz), 6.64 (1H, d, J=7.9 Hz), 6.87 (1H, t, J=7.8 Hz), 7.25-7.47(2H, m), 7.63-8.20 (4H, m), 8.62-8.80 (2H, m).

Example 312

By the reaction and treatment in the same manner as in Example 82 using1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (1.41 g) and5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.83 g) as starting materials,5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (1.62 g) was obtained.

melting point: 194.7° C.

Example 313

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.79 g) and 2-(chloromethyl)pyridine hydrochloride (0.49 g) as startingmaterials,5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.32 (6H, d, J=6.9 Hz), 1.43-1.58 (1H, m), 1.65-2.02(3H, m), 2.55-2.82 (2H, m), 3.10 (1H, sept, J=6.9 Hz), 3.60-3.70 (1H,m), 4.57 (1H, d, J=14.6 Hz), 4.87 (1H, d, J=14.6 Hz), 5.00 (2H, s), 5.41(2H, s), 6.61-6.77 (2H, m), 6.90 (1H, d, J=7.9 Hz), 7.14-7.48 (10H, m),8.59-8.68 (1H, m), 8.43 (1H, d, J=2.4 Hz), 8.53-8.60 (1H, m).

Example 314

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) as a starting material,8-fluoro-5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.69 g) was obtained. MS (ESI) m/z: 500 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.32 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.63-1.92(3H, m), 2.33-2.60 (2H, m), 3.26-3.44 (1H, m), 3.50-3.65 (1H, m), 4.60(1H, d, J=14.7 Hz), 4.87 (1H, d, J=15.0 Hz), 5.64 (2H, s), 6.58-6.78(2H, m), 7.23 (1H, d, J=7.8 Hz), 7.36 (1H, s), 7.64-7.87 (3H, m),8.00-8.13 (1H, m), 8.19-8.36 (1H, m), 8.44-8.58 (1H, m), 8.78 (1H, d,J=5.1 Hz).

Example 315

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 3-(benzyloxy)-6-(chloromethyl)pyridine (0.81g) as starting materials,5-benzyloxy-N-({1-[(5-(benzyloxy)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.37-1.54 (1H, m), 1.77-2.07(3H, m), 2.60-2.80 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 4.65 (1H, d, J=14.7 Hz), 4.84 (1H, d, J=14.7 Hz), 5.02 (2H, s), 5.09(2H, s), 5.33 (2H, s), 6.54 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=8.1 Hz),6.98 (2H, t, J=8.3 Hz), 7.13-7.48 (15H, m), 8.32 (1H, d, J=2.7 Hz), 8.37(1H, d, J=2.4 Hz).

Example 316

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-({1-[(5-(benzyloxy)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.74 g) as a starting material,5-hydroxy-N-({1-[(5-hydroxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.57 g) was obtained. MS (ESI) m/z: 498 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.70-1.97(3H, m), 2.33-2.63 (2H, m), 3.26-3.67 (2H, m), 4.62-4.93 (2H, m), 5.56(2H, s), 6.48 (1H, d, J=7.6 Hz), 6.65 (1H, d, J=7.8 Hz), 6.88 (1H, t,J=7.8 Hz), 7.28-7.44 (2H, m), 7.68-7.95 (3H, m), 8.08-8.23 (1H, m), 8.37(1H, d, J=2.7 Hz), 8.67-8.83 (1H, m).

Example 317

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-chloromethyl-5-ethylpyridine (0.58 g) asstarting materials,5-benzyloxy-N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.6 Hz), 1.30 (6H, d, J=6.9 Hz),1.37-1.55 (1H, m), 1.77-2.07 (3H, m), 2.63 (2H, q, J=7.6 Hz), 2.65-2.82(2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.58-3.68 (1H, m), 4.66 (1H, d,J=14.5 Hz), 4.85 (1H, d, J=14.5 Hz), 5.03 (2H, s), 5.37 (2H, s), 6.55(1H, d, J=7.7 Hz), 6.71 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 7.01(1H, t, J=8.2 Hz), 7.17 (1H, d, J=8.4 Hz), 7.25-7.50 (9H, m), 8.38 (1H,d, J=2.3 Hz), 8.40 (1H, d, J=1.9 Hz).

Example 318

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) as a starting material,N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.61 g) was obtained.

MS (ESI) m/z: 510 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.22 (3H, t, J=7.5 Hz), 1.29 (6H, d, J=6.9 Hz),1.32-1.53 (1H, m), 1.70-1.97 (3H, m), 2.33-2.57 (2H, m), 2.74 (2H, q,J=7.5 Hz), 3.20-3.37 (1H, m), 3.43-3.63 (1H, m), 4.62-4.90 (2H, m), 5.63(2H, s), 6.48 (1H, d, J=7.5 Hz), 6.64 (1H, d, J=7.8 Hz), 6.87 (1H, t,J=7.8 Hz), 7.28 (1H, d, J=8.1 Hz), 7.32-7.42 (1H, m), 7.65-7.91 (2H, m),8.02-8.27 (2H, m), 8.57-8.77 (2H, m).

Example 319

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-chloromethyl-3-methylpyridine (0.53 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.75 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.54 (1H, m), 1.72-2.07(3H, m), 2.30 (3H, s), 2.59-2.79 (2H, m), 3.08 (1H, sept, J=6.9 Hz),3.56-3.66 (1H, m), 4.63 (1H, d, J=14.4 Hz), 4.81 (1H, d, J=14.4 Hz),5.03 (2H, s), 5.42 (2H, s), 6.54 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=8.1Hz), 6.93-7.03 (1H, m), 7.09-7.19 (2H, m), 7.23-7.50 (9H, m), 8.36 (1H,d, J=2.1 Hz), 8.42 (1H, dd, J=1.2, 4.8 Hz).

Example 320

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.74 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.65 g) was obtained.

MS (ESI) m/z: 496 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.32-1.52 (1H, m), 1.70-1.97(3H, m), 2.30 (3H, s), 2.38-2.60 (2H, m), 3.17-3.33 (1H, m), 3.43-3.60(1H, m), 4.60-4.86 (2H, m), 5.70 (2H, s), 6.46 (1H, d, J=7.5 Hz), 6.63(1H, d, J=7.8 Hz), 6.87 (1H, t, J=7.8 Hz), 7.23-7.37 (1H, m,), 7.58-8.09(4H, m), 8.25 (1H, d, J=7.8 Hz), 8.54-8.70 (2H, m).

Example 321

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.81 g) and 2-chloromethyl-4-methylpyridine (0.54 g) asstarting materials,5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.43-1.57 (1H, m), 1.67-2.03(3H, m), 2.31 (3H, s), 2.57-2.84 (2H, m), 3.09 (1H, sept, J=6.9 Hz),3.60-3.72 (1H, m), 4.58 (1H, d, J=14.4 Hz), 4.87 (1H, d, J=14.4 Hz),5.00 (2H, s), 5.36 (2H, s), 6.62-6.77 (3H, m), 7.02 (1H, d, J=4.8 Hz),7.19 (1H, d, J=8.1 Hz), 7.24-8.07 (8H, m), 8.35-8.45 (2H, m).

Example 322

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,8-fluoro-5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.64 g) was obtained.

MS (ESI) m/z: 514 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.56 (1H, m), 1.61-1.93(3H, m), 2.33-2.59 (5H, m), 3.18-3.37 (1H, m), 3.50-3.63 (1H, m), 4.59(1H, d, J=14.7 Hz), 4.84 (1H, d, J=14.7 Hz), 5.68 (2H, s), 6.60-6.77(3H, m), 7.26 (1H, s), 7.36 (1H, m), 7.63-8.05 (4H, m), 8.41-8.53 (1H,m), 8.73 (1H, d, J=6.0 Hz).

Example 323

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-chloromethyl-4-trifluoromethylpyridine(0.67 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.79 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.40-1.57 (1H, m), 1.75-2.07(3H, m), 2.59-2.81 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.59-3.68 (1H,m), 4.69 (1H, d, J=14.7 Hz), 4.85 (1H, d, J=14.7 Hz), 5.03 (2H, s), 5.48(2H, s), 6.54 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=8.1 Hz), 7.00 (1H, t,J=7.8 Hz), 7.10-7.47 (10H, m), 7.55 (1H, s), 8.42 (1H, d, J=2.4 Hz),8.76 (1H, d, J=5.1 Hz).

Example 324

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.78 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.63 g) was obtained. MS (ESI) m/z: 550 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.29 (6H, d, J=6.9 Hz), 1.35-1.53 (1H, m), 1.68-1.95(3H, m), 2.35-2.59 (2H, m), 3.16-3.34 (1H, m), 3.44-3.62 (1H, m),4.63-4.92 (2H, m), 5.53 (2H, s), 6.46 (1H, d, J=7.5 Hz), 6.63 (1H, d,J=7.8 Hz), 6.85 (1H, t, J=7.8 Hz), 7.28-7.42 (2H, m), 7.60-8.06 (4H, m),8.58-8.75 (1H, m), 8.84 (1H, d, J=5.1 Hz).

Example 325

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 5-butyl-2-chloromethylpyridine (0.66 g) asstarting materials,5-benzyloxy-N-({1-[(5-butylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.2 Hz), 1.21-1.68 (11H, m), 1.78-2.07(3H, m), 2.59 (2H, t, J=7.2 Hz), 2.67-2.79 (2H, m), 3.08 (1H, sept,J=6.9 Hz), 3.57-3.67 (1H, m), 4.66 (1H, d, J=14.4 Hz), 4.85 (1H, d,J=14.4 Hz), 5.03 (2H, s), 5.34 (2H, s), 6.55 (1H, d, J=7.8 Hz), 6.71(1H, d, J=8.1 Hz), 6.89 (1H, d, J=7.8 Hz), 7.01 (1H, t, J=7.8 Hz), 7.17(1H, d, J=8.1 Hz), 7.24-7.48 (10H, m), 8.38 (1H, s).

Example 326

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(5-butylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,N-({1-[(5-butylpyridin-5-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.62 g) was obtained.

MS (ESI) m/z: 538 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.90 (3H, t, J=7.2 Hz), 1.18-1.63 (11H, m),1.71-1.97 (3H, m), 2.37-2.60 (2H, m), 2.70 (2H, t, J=7.2 Hz), 3.13-3.32(1H, m), 3.43-3.61 (1H, m), 4.72 (1H, d, J=13.5 Hz), 4.82 (1H, d, J=14.7Hz), 5.59 (2H, s), 6.47 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz), 6.87(1H, t, J=7.8 Hz), 7.21 (1H, d, J=8.1 Hz), 7.29-7.42 (1H, m), 7.58-8.19(4H, m), 8.55-8.72 (2H, m).

Example 327

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 3-chloromethyl-2,6-dimethoxypyridine (0.56 g)as starting materials,5-benzyloxy-N-({1-[(2,6-dimethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38-1.55 (1H, m), 1.76-2.08(3H, m), 2.60-2.81 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.57-3.67 (1H,m), 3.90 (3H, s), 3.94 (3H, s), 4.63 (1H, d, J=14.4 Hz), 4.80 (1H, d,J=14.4 Hz), 5.03 (2H, s), 5.15 (2H, s), 6.27 (1H, d, J=8.1 Hz), 6.53(1H, d, J=7.8 Hz), 6.72 (1H, d, J=8.1 Hz), 7.01 (1H, t, J=7.8 Hz), 7.16(1H, d, J=8.1 Hz), 7.23-7.44 (9H, m), 8.37 (1H, d, J=2.4 Hz).

Example 328

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(2,6-dimethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.68 g) as a starting material,N-({1-[(2,6-dimethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.16 g) was obtained. MS (ESI) m/z: 542 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.26 (6H, d, J=6.9 Hz), 1.30-1.50 (1H, m), 1.69-1.95(3H, m), 2.32-2.59 (2H, m), 3.07-3.26 (1H, m), 3.40-3.57 (1H, m), 3.85(3H, s), 3.88 (3H, s), 4.58-4.85 (2H, m), 5.12 (2H, s), 6.35 (1H, d,J=8.1 Hz), 6.43 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.8 Hz), 6.86 (1H, t,J=7.7 Hz), 7.26 (2H, d, J=8.1 Hz), 7.43-7.62 (2H, m), 7.75-7.92 (1H, m),8.43-8.63 (1H, m).

Example 329

By the reaction and treatment in the same manner as in Example 132 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.20 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as startingmaterials,5-benzyloxy-N-[(2-ethylthiazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.30 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.38 (3H, t, J=7.5 Hz),1.45-1.57 (1H, m), 1.83-2.08 (3H, m), 2.60-2.81 (2H, m), 3.01 (2H, q,J=7.5 Hz), 3.07 (1H, sept, J=6.9 Hz), 3.68-3.78 (1H, m), 4.88 (1H, d,J=14.7 Hz), 5.02 (2H, s), 5.09 (1H, d, J=14.7 Hz), 6.63 (1H, d, J=7.8Hz), 6.71 (1H, d, J=8.1 Hz), 7.03 (1H, t, J=7.8 Hz), 7.10 (1H, s), 7.20(1H, d, J=8.1 Hz), 7.23-7.45 (5H, m), 7.60 (1H, dd, J=2.7, 8.4 Hz), 8.47(1H, d, J=2.4 Hz).

Example 330

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-[(2-ethylthiazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.28 g) as a starting material,N-[(2-ethylthiazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.85 g) was obtained.

MS (ESI) m/z: 436 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.24-1.57 (10H, m), 1.73-2.00 (3H, m), 2.32-2.60(2H, m), 2.98 (2H, q, J=7.4 Hz), 3.19-3.45 (1H, m), 3.52-3.70 (1H, m),4.80-5.11 (2H, m), 6.40-6.58 (1H, m), 6.63 (1H, d, J=7.8 Hz), 6.87 (1H,t, J=7.8 Hz), 7.30-8.02 (2H, m), 8.22-8.48 (1H, m), 8.80-8.93 (1H, m).

Example 331

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) asstarting materials,5-benzyloxy-N-({1-[(2-ethylthiazol-4-yl}methyl]pyrazol-4-yl)methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.37 (3H, t, J=7.5 Hz),1.41-1.57 (1H, m), 1.77-2.08 (3H, m), 2.60-2.80 (2H, m), 3.01 (2H, q,J=7.5 Hz), 3.09 (1H, sept, J=6.9 Hz), 3.59-3.68 (1H, m), 4.66 (1H, d,J=14.4 Hz), 4.84 (1H, d, J=14.7 Hz), 5.03 (2H, s), 5.26 (2H, s), 6.55(1H, d, J=7.8 Hz), 6.72 (1H, d, J=8.1 Hz), 6.82 (1H, s), 7.03 (1H, t,J=7.8 Hz), 7.18 (1H, d, J=8.4 Hz), 7.22-7.50 (8H, m), 8.38 (1H, d, J=2.4Hz).

Example 332

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[(2-ethylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.65 g) as a starting material,N-({1-[(2-ethylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.56 g) was obtained. MS (ESI) m/z: 516 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.18-1.52 (10H, m), 1.70-1.97 (3H, m), 2.34-2.60(2H, m), 2.95 (2H, q, J=7.5 Hz), 3.18-3.39 (1H, m), 3.45-3.62 (1H, m),4.60-4.88 (2H, m), 5.32 (2H, s), 6.47 (1H, d, J=7.5 Hz), 6.63 (1H, d,J=7.8 Hz), 6.87 (1H, t, J=7.8 Hz), 7.14 (1H, s), 7.22-7.38 (1H, m),7.57-7.81 (2H, m), 7.97-8.13 (1H, m), 8.60-8.88 (1H, m).

Example 333

By the reaction and treatment in the same manner as in Example 82 using1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (1.74 g) andN-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.15 g) as starting materials,N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (1.99 g) was obtained. melting point: 217.3° C.

¹H-NMR (CDCl₃) δ: 1.36 (6H, d, J=6.9 Hz), 1.42-1.60 (1H, m), 1.75-2.00(3H, m), 2.55-2.80 (2H, m), 3.52 (1H, sept, J=6.9 Hz), 3.60-3.77 (1H,m), 4.70-5.02 (2H, m), 6.98-7.18 (4H, m), 7.85 (2H, s), 8.00 (1H, d,J=8.7 Hz), 8.33-8.53 (1H, m), 8.98 (1H, d, J=2.1 Hz).

Example 334

To a solution ofN-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.99 g) in methylene chloride (10 mL) were addedtetra-n-butylammonium hydrogensulfate (0.82 g),2-chloromethyl-4-methylpyridine hydrochloride (0.86 gland 1mol/L-aqueous sodium hydroxide solution (24.0 mL). The mixture wasstirred at room temperature for one day. The reaction mixture waspartitioned between water and chloroform. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography to giveN-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide.This compound was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane(2.4 mL) was added. The precipitated solid was collected by filtrationto giveN-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.61 g).

MS (ESI) m/z: 480 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.38-1.60 (1H, m), 1.72-2.00(3H, m), 2.50 (3H, s), 2.57-2.80 (2H, m), 3.23-3.42 (1H, m), 3.53-3.68(1H, m), 4.60-4.94 (2H, m), 5.45 (2H, s), 6.95-7.20 (5H, m), 7.27-7.43(1H, m), 7.60-7.93 (3H, m), 8.01-8.22 (1H, m), 8.40 (1H, d, J=2.7 Hz),8.67-8.85 (1H, m).

Example 335

By the reaction and treatment in the same manner as in Example 334 usingN-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.95 g) and 2-chloromethyl-5-methoxypyridine (0.83 g) asstarting materials,N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.97 g) was obtained.

MS (ESI) m/z: 496 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.37-1.59 (1H, m), 1.77-2.02(3H, m), 2.46-2.82 (5H, m), 3.21-3.42 (1H, m), 3.52-3.71 (1H, m),4.60-4.98 (2H, m), 5.70 (2H, s), 6.98-7.17 (4H, m), 7.28-7.52 (2H, m),7.75 (2H, d, J=5.4 Hz), 7.85-8.00 (1H, m), 8.09-8.26 (1H, m), 8.74 (2H,d, J=6.0 Hz).

Example 336

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.78 g) and 6-chloromethyl-2-(dimethylamino)pyridine (0.46 g) asstarting materials,5-benzyloxy-N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.39-1.63 (1H, m), 1.77-2.08(3H, m), 2.60-2.83 (2H, m), 3.05 (6H, s), 3.08 (1H, sept, J=6.9 Hz),3.57-3.67 (1H, m), 4.66 (1H, d, J=14.4 Hz), 4.85 (1H, d, J=14.4 Hz),5.03 (2H, s), 5.22 (2H, s), 6.19 (1H, d, J=7.2 Hz), 6.40 (1H, d, J=8.4Hz), 6.55 (1H, d, J=7.5 Hz), 6.71 (1H, d, J=8.1 Hz), 7.01 (1H, t, J=8.0Hz), 7.16 (1H, d, J=8.4 Hz), 7.23-7.44 (8H, m), 7.51 (1H, s), 8.40 (1H,d, J=2.1 Hz).

Example 337

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) as a starting material,N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.30 g) was obtained. MS (ESI) m/z: 525 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.33-1.51 (1H, m), 1.70-1.96(3H, m), 2.35-2.60 (2H, m), 3.15-3.32 (1H, m), 3.17 (6H, m), 3.43-3.64(1H, m), 4.72 (1H, d, J=14.1 Hz), 4.81 (1H, d, J=14.4 Hz), 5.46 (2H, s),6.09 (1H, d, J=7.2 Hz), 6.46 (1H, d, J=7.5 Hz), 6.63 (1H, d, J=7.8 Hz),6.82-6.97 (2H, m), 7.30-7.43 (1H, m), 7.57-7.85 (3H, m), 7.90-8.07 (1H,m), 8.55-8.68 (1H, m).

Example 338

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 3-(dimethylamino)benzyl chloride (0.51 g) asstarting materials,5-benzyloxy-N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.46 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.39-1.55 (1H, m), 1.75-2.07(3H, m), 2.58-2.80 (2H, m), 2.93 (6H, s), 3.08 (1H, sept, J=6.9 Hz),3.57-3.67 (1H, m), 4.61 (1H, d, J=14.4 Hz), 4.84 (1H, d, J=14.7 Hz),5.03 (2H, s), 5.20 (2H, s), 6.47-6.59 (3H, m), 6.62-6.75 (2H, m),6.95-7.04 (1H, m), 7.11-7.45 (10H, m), 8.38 (1H, d, J=2.4 Hz).

Example 339

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.46 g) as a starting material,N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.33 g) was obtained. MS (ESI) m/z: 524 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.33-1.50 (1H, m), 1.67-1.93(3H, m), 2.33-2.57 (2H, m), 3.00 (6H, s), 3.11-3.31 (1H, m), 3.42-3.63(1H, m), 4.60-4.86 (2H, m), 5.28 (2H, s), 6.45 (1H, d, J=7.8 Hz), 6.63(1H, d, J=7.8 Hz), 6.75-6.90 (2H, m), 7.17-7.41 (4H, m), 7.57-7.75 (2H,m), 7.85-8.03 (1H, m), 8.53-8.71 (1H, m).

Example 340

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 2-(dimethylamino)benzyl chloride (0.51 g) asstarting materials,5-benzyloxy-N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.36-1.56 (1H, m), 1.68-2.07(3H, m), 2.66 (6H, s), 2.65-2.81 (2H, m), 3.08 (1H, sept, J=6.9 Hz),3.57-3.67 (1H, m), 4.64 (1H, d, J=14.4 Hz), 4.84 (1H, d, J=14.4 Hz),5.02 (2H, s), 5.40 (2H, s), 6.52 (1H, d, J=7.8 Hz), 6.71 (1H, d, J=8.1Hz), 6.88 (1H, d, J=6.6 Hz), 6.94-7.06 (2H, m), 7.16 (2H, d, J=8.1 Hz),7.22-7.45 (9H, m), 8.38 (1H, d, J=2.4 Hz).

Example 341

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) as a starting material,N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.32 g) was obtained. MS (ESI) m/z: 524 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.31-1.52 (1H, m), 1.70-1.96(3H, m), 2.33-2.59 (2H, m), 3.08 (6H, s), 3.15-3.33 (1H, m), 3.44-3.61(1H, m), 4.62-4.87 (2H, m), 5.68 (2H, s), 6.46 (1H, d, J=7.5 Hz), 6.63(1H, d, J=7.8 Hz), 6.87 (1H, d, J=7.8 Hz), 7.00 (1H, d, J=7.2 Hz),7.27-7.51 (3H, m), 7.60-8.05 (4H, m), 8.57-8.70 (1H, m).

Example 342

By the reaction and treatment in the same manner as in Example 82 usingN-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g) and1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (2.4 g) as startingmaterials,N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxamide(2.9 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 1.90-2.25 (2H, m), 2.85-3.05(1H, m), 3.60-3.85 (2H, m), 4.05-4.25 (1H, m), 4.50-4.70 (1H, m), 4.72(1H, d, J=14.4 Hz), 4.80 (1H, d, J=14.4 Hz), 6.87 (1H, t, J=7.9 Hz),7.00-7.15 (3H, m), 7.20-7.35 (2H, m), 7.49 (2H, s), 7.70 (1H, d, J=1.4Hz).

Example 343

By the reaction and treatment in the same manner as in Example 271 usingN-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxamide(2.9 g) and ethyl iodide (1.1 mL) as starting materials,N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide(2.9 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.2 Hz),1.90-2.05 (1H, m), 2.10-2.20 (1H, m), 2.85-3.05 (1H, m), 3.70-3.80 (1H,m), 4.13 (2H, q, J=7.2 Hz), 4.05-4.25 (1H, m), 4.50-4.65 (1H, m), 4.64(1H, d, J=14.1 Hz), 4.75 (1H, d, J=14.1 Hz), 6.87 (1H, t, J=7.8 Hz),6.95-7.10 (3H, m), 7.20-7.40 (4H, m) 7.65-7.75 (1H, m).

Example 344

To a mixed solvent of ethanol (43 mL) and water (18 mL) were added iron(0.43 g) and ammonium chloride (0.06 g), and a solution ofN-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide(0.9 g) in ethanol (10 mL) was added dropwise with heating and stirringat 50° C.-70° C. After stirring at 50° C.-70° C. for 3 hr, the reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated brine and dried over magnesium sulfate.The solvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give8-amino-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(0.66 g).

1H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 1.45 (3H, t, J=7.3 Hz),1.85-2.00 (1H, m), 2.10-2.25 (1H, m), 2.85-3.00 (1H, m), 3.60-3.80 (3H,m), 4.00-4.20 (1H, m), 4.12 (2H, q, J=7.3 Hz), 4.45-4.55 (1H, m), 4.60(1H, d, J=14.4 Hz), 4.81 (1H, d, J=14.4 Hz), 6.30 (1H, d, J=7.5 Hz),6.50-6.56 (1H, m), 6.63 (1H, t, J=7.6 Hz), 6.95-7.40 (6H, m).

Example 345

By the reaction and treatment in the same manner as in Example 82 using4-benzyloxy-N-(2,4-dimethoxyphenyl)indan-1-carboxamide (0.96 g) and1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.47 g) as startingmaterials,4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(pyrazol-4-yl)methyl]indan-1-carboxamide(0.43 g) was obtained. By the reaction and treatment in the same manneras in Example 271 using this compound (0.43 g) and ethyl iodide (0.28mL),4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]indan-1-carboxamide(0.36 g) was obtained. By the reaction and treatment in the same manneras in Example 17 using this compound (0.36 g),N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxyindan-1-carboxamide(0.21 g) was obtained.

MS (ESI) m/z: 422 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.44 (3H, t, J=7.2 Hz), 2.00-2.50 (2H, m), 2.55-2.80(1H, m), 2.90-3.20 (1H, m), 3.55-4.40 (8H, m), 4.11 (2H, q, J=7.2 Hz),5.00-5.25 (1H, m), 5.90-7.50 (9H, m).

Example 346

By the reaction and treatment in the same manner as in Example 12 using7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.51 g) asstarting materials,N-[(1-ethylpyrazol-4-yl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.46 (3H,t, J=7.2 Hz), 1.80-2.15 (3H, m), 2.55-3.05 (3H, m), 3.60-3.75 (1H, m),4.14 (2H, q, J=7.2 Hz), 4.59 (1H, d, J=14.4 Hz), 4.83 (1H, d, J=14.4Hz), 6.55-6.65 (1H, m), 6.75-6.85 (1H, m), 6.95-7.10 (3H, m), 7.20-7.40(2H, m), 7.31 (1H, s), 7.43 (1H, s).

Example 347

By the reaction and treatment in the same manner as in Example 12 using8-cyanochroman-4-carboxylic acid (0.7 g) and[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.84 g) asstarting materials,8-cyano-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide(1.2 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=7.0 Hz), 1.45 (3H, t, J=7.4 Hz),1.85-2.20 (2H, m), 2.85-3.05 (1H, m), 3.70-3.80 (1H, m), 4.05-4.25 (1H,m), 4.12 (2H, q, J=7.4 Hz), 4.63 (1H, d, J=14.3 Hz), 4.75 (1H, d, J=14.3Hz), 4.50-4.70 (1H, m), 6.85 (1H, t, J=7.7 Hz), 7.00-7.15 (3H, m),7.20-7.50 (5H, m).

Example 348

By the reaction and treatment in the same manner as in Example 82 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.75 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.84g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.22 g) was obtained.

MS (ESI) m/z: 495 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.33 (6H, d, J=6.9 Hz), 1.50-1.80 (2H, m), 1.82-2.10(2H, m), 2.05 (3H, s), 2.45-2.60 (1H, m), 2.80-3.20 (2H, m), 3.50-3.60(1H, m), 4.57 (1H, d, J=14.5 Hz), 4.86 (1H, d, J=14.5 Hz), 5.01 (2H, s),6.68 (1H, d, J=8.3 Hz), 6.88 (1H, d, J=8.2 Hz), 7.20-7.55 (9H, m), 8.45(1H, d, J=2.4 Hz).

Example 349

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.5 g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.36 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.45 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.33 (6H, d, J=6.9 Hz), 1.55-1.75 (2H, m), 1.80-2.00(2H, m) 2.03 (3H, s), 2.31 (3H, s), 2.45-2.60 (1H, m), 2.85-3.00 (1H,m), 3.02-3.20 (1H, m), 3.50-3.60 (1H, m), 4.54 (1H, d, J=14.5 Hz), 4.82(1H, d, J=14.5 Hz), 5.01 (2H, s), 5.35 (2H, s), 6.67 (1H, d, J=8.3 Hz),6.79 (1H, s), 6.87 (1H, d, J=8.3 Hz), 7.02 (1H, d, J=4.8 Hz), 7.15-7.50(9H, m), 8.41 (1H, d, J=5.0 Hz), 8.46 (1H, d, J=2.4 Hz).

Example 350

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.45 g) as starting materials,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.27 g) was obtained. MS (ESI) m/z: 510 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.40-2.05 (4H, m), 1.92 (3H,s), 2.20-2.70 (5H, m), 3.10-3.25 (1H, m), 3.40-3.50 (1H, m), 4.60 (1H,d, J=14.4 Hz), 4.75 (1H, d, J=14.4 Hz), 5.60 (2H, s), 6.54 (1H, d, J=7.2Hz), 6.70 (1H, d, J=8.1 Hz), 7.17 (1H, brs), 7.34 (1H, brs), 7.50-7.95(4H, m), 8.51 (1H, brs), 8.67 (1H, d, J=5.7 Hz).

Example 351

By the reaction and treatment in the same manner as in Example 142 using2-ethyl-5-hydroxymethyl-4-methylthiazole (0.63 g) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.8 g) as starting materials,5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.3 g) was obtained.

MS (ESI) m/z: 540 [MH]⁺

Example 352

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.3 g) as a starting material,N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) was obtained.

MS (ESI) m/z: 450 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.26 (6H, d, J=6.9 Hz), 1.26 (3H, t, J=7.5 Hz),1.30-1.50 (1H, m), 1.70-2.00 (3H, m), 1.94 (3H, s), 2.35-2.60 (2H, m),2.94 (2H, q, J=7.5 Hz), 3.10-3.25 (1H, m), 3.40-3.60 (1H, m), 4.92 (1H,d, J=14.6 Hz), 5.04 (1H, d, J=14.6 Hz), 6.45 (1H, d, J=7.5 Hz), 6.63(1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.8 Hz), 7.56 (1H, d, J=8.1 Hz),7.75-7.90 (1H, m), 8.52 (1H, brs).

Example 353

By the reaction and treatment in the same manner as in Example 142 using2-ethyl-5-hydroxymethyl-4-trifluoromethylthiazole (0.63 g) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.2 g) as starting materials,5-benzyloxy-N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.4 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.40 (3H, t, J=7.5 Hz),1.45-1.65 (1H, m), 1.80-2.10 (3H, m), 2.65-2.80 (2H, m), 3.02 (2H, q,J=7.5 Hz), 2.95-3.20 (1H, m), 3.65-3.80 (1H, m), 5.04 (2H, s), 5.19 (2H,s), 6.59 (1H, d, J=7.8 Hz), 6.75 (1H, d, J=7.8 Hz), 7.08 (1H, t, J=7.8Hz), 7.20-7.45 (7H, m), 8.37 (1H, d, J=2.4 Hz).

Example 354

By the reaction and treatment in the same manner as in Example 133 using5-benzyloxy-N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.4 g) as a starting material,N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.22 g) was obtained.

melting point: 164.0° C.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=7.0 Hz), 1.40 (3H, t, J=7.6 Hz),1.45-1.70 (1H, m), 1.80-2.20 (3H, m), 2.50-2.75 (2H, m), 3.03 (2H, q,J=7.6 Hz), 3.00-3.20 (1H, m), 3.65-3.80 (1H, m), 5.19 (2H, s), 5.58 (1H,s), 6.45-6.60 (2H, m), 6.93 (1H, t, J=7.8 Hz), 7.20-7.50 (2H, m), 8.37(1H, d, J=2.4 Hz).

Example 355

To a solution of5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.35 g) in dimethylformamide were added 2-chloro-N,N-dimethylethylaminehydrochloride (0.12 g) and sodium hydride (0.035 g), and the mixture wasstirred for one day. The reaction mixture was partitioned between waterand ethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was evaporated, and theobtained residue was reacted and treated in the same manner as inExample 17 to giveN-({1-[2-(dimethylamino)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.18 g). melting point: 92° C.

Example 356

By the reaction and treatment in the same manner as in Example 17 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g) as a starting material,5-hydroxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.14 g) was obtained. melting point: 247° C.

Example 357

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) and isopropyl iodide (0.16 mg) as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.47 g) was obtained. By the reaction and treatment of this compound,in the same manner as in Example 175-hydroxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.22 g) was obtained. melting point: 185° C.

Example 358

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.50 mg) and bromocyclopentane (0.12 mL) as starting materials,5-benzyloxy-N-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.54 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 17,N-[(1-cyclopentylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.27 g) was obtained. melting point: 173° C.

Example 359

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) and methyl iodide (0.073 mL) as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.49 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 17,5-hydroxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) was obtained. melting point: 215° C.

Example 360

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.50 g) and 1-bromopropane (0.1 mL) as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 17,5-hydroxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained. melting point: 161° C.

Example 361

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.12 g) and ethyl bromoacetate (0.31 mL), ethyl2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetate(0.66 g) was obtained. This compound was dissolved in ethanol (20 mL),and 1 mol/L-aqueous sodium hydroxide solution (1.22 mL) was added. Themixture was stirred at room temperature for 1 hr. To the reactionmixture was added 1 mol/L-hydrochloric acid (1.22 mL), and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated. By the reaction and treatment of the obtained residue inthe same manner as in Example 17 (0.58 g),2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)aceticacid (0.23 g) was obtained. melting point: 180-182° C.

Example 362

Ethyl2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetate(1.0 g) was dissolved in tetrahydrofuran:ethanol (1:2) solution (10 mL),and lithium chloride (0.30 g) and sodium borohydride (0.27 g) wereadded. The mixture was stirred at room temperature for 3 hr. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was evaporated, and the obtained residue (0.91 g)was reacted and treated in the same manner as in Example 17 to give5-hydroxy-N-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.25 g). melting point: 110-114° C.

Example 363

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.02 g) and 1-bromo-3-(2-oxanyloxy)propane (0.45 mL) as startingmaterials,5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(2-oxanyloxy)propyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.65 g) was obtained. This compound was dissolved in methanol (30 mL),and 4 mol/L-HCl/dioxane (0.1 mL) was added. The mixture was stirred atroom temperature for 2 hr. Into the reaction mixture was pouredsaturated aqueous sodium hydrogencarbonate (2 mL). The reaction mixturewas concentrated under reduced pressure and partitioned between waterand ethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was evaporated. By thereaction and treatment of the obtained residue (0.94 g) in the samemanner as in Example 105,5-hydroxy-N-{[1-(3-hydroxypropyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) was obtained.

¹H-NMR (CDCl₃) δ: 2.48 (6H, d, J=6.9 Hz), 1.41-1.44 (1H, m), 1.82-1.98(5H, m), 2.57 (2H, brs), 2.92 (1H, sept, J=6.9 Hz), 3.48-3.52 (2H, m),3.68-3.73 (1H, m), 4.19 (2H, t, J=6.2 Hz), 4.57 (1H, d, J=14.3 Hz), 4.83(1H, d, J=14.3 Hz), 6.40 (2H, t, J=8.7 Hz), 6.80 (1H, t, J=7.8 Hz), 7.07(2H, d, J=8.1 Hz), 7.22-7.26 (2H, m), 7.34 (1H, s), 7.47 (1H, s), 8.14(1H, brs).

Example 364

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.33 g) and (bromomethyl)cyclohexane (0.142 mL) as starting materials,5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.26 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 105,N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.18 g) was obtained.

¹H-NMR (DMSO-d₆) δ: (0.84-(0.92 (2H, m), 1.11-1.44 (12H, m), 1.63-1.77(6H, m), 1.91-1.99 (1H, m), 2.43-2.52 (2H, m), 2.89 (1H, sept, J=6.9Hz), 3.50-3.55 (1H, m), 3.86 (2H, d, J=7.2 Hz), 4.65 (2H, s), 6.40 (1H,d, J=7.8 Hz), 6.59 (1H, d, J=7.8 Hz), 6.86 (1H, t, J=7.8 Hz), 7.12 (2H,d, J=8.4 Hz), 7.21 (1H, s), 7.28 (2H, d, J=8.4 Hz), 7.41 (1H, s).

Example 365

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.37 g) and 3-(chloromethyl)thiophene (0.21 g) as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.16 g) was obtained. By the reaction and treatment of this compound(0.11 g), in the same manner as in Example 133,5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.054 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.38-1.45 (1H, m), 1.76-2.01(3H, m), 2.55-2.60 (2H, m), 2.92 (1H, sept, J=6.9 Hz), 3.67-3.72 (1H,m), 4.67 (1H, d, J=14.4 Hz), 4.79 (1H, d, J=14.4 Hz), 5.23 (2H, s), 6.33(1H, d, J=7.8 Hz); 6.38 (1H, d, J=7.8 Hz), 6.74 (1H, t, J=7.8 Hz),6.94-6.96 (1H, m), 7.04 (2H, d, J=8.1 Hz), 7.11-7.12 (1H, m), 7.20-7.30(3H, m), 7.41 (2H, s), 7.53 (1H, brs).

Example 366

By the reaction and treatment in the same manner as in Example 82 using5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.98 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (1.83 g)as starting materials,5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.74 g) was obtained.

MS (ESI) m/z: 468 [MH]⁺

Example 367

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.56 g) and 4-fluorobenzyl chloride (0.172 mL) as starting materials,5-benzyloxy-N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.60 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 133,N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.42 g) was obtained.

melting point: 143-146° C.

Example 368

By the reaction and treatment in the same manner as in example 83 using5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.62 g) and ethyl iodide (0.13 mL) as starting materials,5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.55 g) was obtained. By the reaction and treatment of this compound(0.40 g) in the same manner as in Example 133,N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.30 g) was obtained. melting point: 211-213° C.

Example 369

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.56 g) and (bromomethyl)cyclohexane (0.20 mL) as starting materials,5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.55 g) was obtained. By the reaction and treatment in the same manneras in Example 133 using this compound (0.45 g),N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.36 g) was obtained.

¹H-NMR (DMSO-d₆) δ: 0.84-0.92 (2H, m), 1.12-1.23 (3H, m), 1.32-1.46 (3H,m), 1.63-1.75 (6H, m), 1.90-1.94 (1H, m), 2.40-2.56 (2H, m), 3.53-3.58(1H, m), 3.74 (3H, s), 3.83 (2H, d, J=1 (0.8 Hz), 4.60 (1H, d, J=14.7Hz), 4.66 (1H, d, J=14.7 Hz), 6.40 (1H, d, J=7.8 Hz), 6.62 (1H, d, J=7.8Hz), 6.86 (1H, t, J=78 Hz), 6.93-6.96 (2H, m), 7.10-7.13 (2H, m), 7.20(1H, s), 7.41 (1H, s), 9.19 (1H, s).

Example 370

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.77 g) and 4-(chloromethyl)pyridine (0.49 g) as startingmaterials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.58 g) was obtained.

MS (ESI) m/z: 482 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.9 Hz), 1.35-1.43 (1H, m), 1.80-2.00(3H, m), 2.38-2.55 (2H, m), 3.22-3.28 (1H, m), 3.53 (1H, brs), 4.73 (1H,d, J=14.3 Hz), 4.84 (1H, d, J=14.3 Hz), 5.68 (2H, s), 6.47 (1H, d, J=7.8Hz), 6.64 (1H, d, J=7.8 Hz), 6.87 (1H, d, J=7.8 Hz), 7.43 (1H, s), 7.57(2H, d, J=6.6 Hz), 7.66-7.69 (1H, m), 7.83 (1H, s), 8.00 (1H, brs), 8.61(1H, brs), 8.89 (2H, d, J=6.6 Hz).

Example 371

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.77 g) and 1-(2-chloroethyl)piperidine hydrochloride(0.55 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.54 g) was obtained.

MS (ESI) m/z: 502 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.32-1.40 (1H, m), 1.65-1.91(7H, m), 2.47-2.52 (3H, m), 2.81-2.86 (2H, m), 3.18-3.57 (5H, m), 4.61(2H, d, J=6.6 Hz), 4.63-4.87 (2H, m), 5.10 (2H, brs), 6.49 (1H, d, J=7.8Hz), 6.66 (1H, d, J=7.8 Hz), 6.88 (1H, t, J=7.8 Hz), 7.36 (1H, brs),7.76 (2H, brs), 8.15 (1H, brs), 8.68 (1H, brs), 11.1 (1H, brs).

Example 372

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.72 g) and (bromomethyl)cyclohexane (0.25 mL) asstarting materials,5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.86 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.63 g) was obtained.

MS (ESI) m/z: 487 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.83-1.91 (21H, m), 2.46-2.52 (2H, m), 3.23 (1H,brs), 3.52 (1H, brs), 3.86 (2H, d, J=7.1 Hz), 4.74 (2H, brs), 6.45 (1H,d, J=7.8 Hz), 6.63 (1H, d, J=7.8 Hz), 6.88 (1H, t, J=7.8 Hz), 7.26 (1H,brs), 7.49 (1H, brs), 7.65 (1H, brs), 7.93 (1H, brs), 8.61 (1H, brs).

Example 373

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.72 g) and 1-bromoheptane (0.283 mL) as startingmaterials,5-benzyloxy-N-[(1-heptylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.86 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-[(1-heptylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.62 g) was obtained.

MS (ESI) m/z: 489 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.82-(0.87 (3H, m), 1.10-1.43 (15H, m), 1.63-1.91(5H, m), 2.46-2.54 (2H, m), 3.31 (1H, brs), 3.54 (1H, brs), 4.02 (2H, t,J=6.9 Hz), 4.72-4.77 (2H, m), 6.47 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=7.8Hz), 6.88 (1H, t, J=7.8 Hz), 7.27 (1H, brs), 7.55 (1H, brs), 7.74 (1H,brs), 8.03 (1H, brs), 8.68 (1H, brs).

Example 374

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.72 g) and3-chloromethyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (0.38 g)as starting materials,5-benzyloxy-N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.92 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.50 g) was obtained.

MS (ESI) m/z: 529 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.28 (6H, d, J=6.8 Hz), 1.34-1.44 (1H, m), 1.80-1.91(3H, m), 2.46-2.55 (2H, m), 3.21 (1H, brs), 3.51 (1H, brs), 4.11-4.29(4H, m), 4.66-4.81 (2H, m), 5.35 (2H, m), 6.45 (1H, d, J=7.8 Hz), 6.64(1H, d, J=7.8 Hz), 6.81-6.91 (2H, m), 7.37 (1H, brs), 7.59-7.61 (1H, m),7.74 (1H, brs), 7.93 (1H, brs), 8.85 (1H, brs), 9.98 (1H, brs).

Example 375

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.72 g) and (bromomethyl)cyclopropane (0.174 mL) asstarting materials,5-benzyloxy-N-{[1-(cyclopropylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.80 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-{[1-(cyclopropylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.58 g) was obtained.

MS (ESI) m/z: 445 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.26-(0.30 (2H, m), 0.45-(0.51 (2H, m), 1.12-1.20(1H, m), 1.32 (6H, d, J=6.9 Hz), 1.40-1.50 (1H, m), 1.81-1.91 (3H, m),2.47-2.51 (2H, m), 3.34 (1H, brs), 3.55 (1H, brs), 3.91 (2H, d, J=6.9Hz), 4.76 (2H, brs), 6.49 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.8 Hz),6.89 (1H, t, J=7.8 Hz), 7.28 (1H, brs), 7.59 (1H, brs), 7.79 (1H, brs),8.07 (1H, brs), 8.70 (1H, brs).

Example 376

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.72 g) and 4-(2-chloroethyl)morpholine hydrochloride(0.33 g) as starting materials,5-benzyloxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.69 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.34 g) was obtained.

MS (ESI) m/z: 504 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.40-1.50 (1H, m), 1.81-1.91(3H, m), 2.43-2.54 (2H, m), 3.05 (1H, brs), 3.24 (1H, brs), 3.52-3.57(4H, m), 3.81-3.89 (4H, m), 4.58-5.20 (6H, m), 6.48 (1H, d, J=7.8 Hz),6.64 (1H, d, J=7.8 Hz), 6.90 (1H, t, J=7.8 Hz), 7.35 (1H, brs),7.47-7.73 (2H, m), 8.05 (1H, brs), 8.63 (1H, brs), 11.7 (1H, brs).

Example 377

To a solution of5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.72 g) in dimethylformamide (5 mL) were addedtriethylamine (0.23 mL) and cyclohexanecarbonyl chloride (0.22 mL), andthe mixture was stirred at room temperature for one day. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with saturated brine and dried over magnesium sulfate.The solvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give5-benzyloxy-N-{[1-(cyclohexylcarbonyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g). By the reaction and treatment of this compound in the samemanner as in Example 139,N-{[1-(cyclohexanecarbonyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.23 g) was obtained.

MS (ESI) m/z: 501 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.15-2.00 (20H, m), 2.43 (2H, brs), 2.58-2.64 (1H,m), 3.40-3.44 (1H, m), 3.66 (1H, brs), 4.73-7.89 (2H, m), 6.89 (1H, d,J=7.8 Hz), 7.01 (1H, d, J=7.8 Hz), 7.16 (1H, t, J=7.8 Hz), 7.57-7.66(2H, m), 7.86-7.89 (2H, m), 8.25-8.26 (1H, m), 8.87 (1H, brs).

Example 378

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) and 3-(chloromethyl)thiophene (0.27 g) asstarting materials,5-benzyloxy-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.48 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.39 g) was obtained.

MS (ESI) m/z: 487 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.8 Hz), 1.42 (1H, m), 1.79-1.91 (3H,m), 2.46-2.51 (2H, m), 3.30 (1H, brs), 3.53-3.57 (1H, m), 4.76 (2H, m),5.26 (2H, s), 6.45 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=7.8 Hz), 6.87-6.94(2H, m), 7.24-7.28 (2H, m), 7.49-7.52 (1H, m), 7.61 (1H, brs), 7.73 (1H,brs), 8.02 (1H, brs), 8.68 (1H, brs).

Example 379

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) and 4-(chloromethyl)-2-methylthiazole (0.55 g) asstarting materials,5-benzyloxy-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.73 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.62 g) was obtained.

MS (ESI) m/z: 502 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.33 (6H, d, J=6.9 Hz), 1.41-1.50 (1H, m), 1.83-1.91(3H, m), 2.41-2.50 (2H, m), 2.63 (3H, s), 3.40-3.45 (1H, m), 3.57 (1H,brs), 4.70-4.85 (2H, m), 5.31 (2H, s), 6.49 (1H, d, J=7.8 Hz), 6.66 (1H,d, J=7.8 Hz), 6.88 (1H, d, J=7.8 Hz), 7.19 (1H, s), 7.32 (1H, brs),7.67-7.70 (1H, m), 7.87-7.89 (1H, m), 8.21 (1H, brs), 8.80 (1H, brs).

Example 380

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) and 1-bromobutane (0.322 mL) as startingmaterials,5-benzyloxy-N-[(1-butylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-[(1-butylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.41 g) was obtained. MS (ESI) m/z: 447 [MH]+

¹H-NMR (DMSO-d₆) δ: 0.82-0.84 (3H, m), 1.07-1.20 (2H, m), 1.35 (6H, d,J=6.9 Hz), 1.40-1.51 (1H, m), 1.62-1.92 (5H, m), 2.47-2.52 (2H, m),3.43-3.57 (2H, m), 3.99-4.06 (2H, m), 4.70-5.20 (2H, m), 6.50 (1H, d,J=7.7 Hz), 6.68 (1H, d, J=7.7 Hz), 6.89 (1H, t, J=7.7 Hz), 7.33 (1H,brs), 7.60 (1H, brs), 7.92-7.95 (1H, m), 8.25 (1H, brs), 8.82 (1H, brs).

Example 381

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) and isobutyl bromide (0.326 mL) as startingmaterials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.16 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 19,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.11 g) was obtained.

MS (ESI) m/z: 447 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.75 (6H, d, J=6.9 Hz), 1.29 (6H, d, J=6.9 Hz),1.35-1.47 (1H, m), 1.81-1.94 (3H, m), 2.46-2.52 (3H, m), 3.29 (1H, brs),3.50-3.60 (1H, m), 3.83 (2H, d, J=6.9 Hz), 4.76 (2H, brs), 6.47 (1H, d,J=7.8 Hz), 6.64 (1H, d, J=7.8 Hz), 6.88 (1H, t, J=7.8 Hz), 7.24-7.31(1H, m), 7.51 (1H, brs), 7.74 (1H, brs), 8.02 (1H, brs), 8.67 (1H, brs).

Example 382

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) and 1-bromo-3-methylbutane (0.359 mL) as startingmaterials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.60 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.45 g) was obtained.

MS (ESI) m/z: 461 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.85 (6H, d, J=6.6 Hz), 1.34 (6H, d, J=6.9 Hz),1.43-1.54 (1H, m), 1.56-1.63 (2H, m), 1.85-1.92 (3H, m), 2.43-2.52 (3H,m), 3.41-3.65 (2H, m), 4.02-4.08 (2H, m), 4.70-5.20 (2H, m), 6.49 (1H,d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.8 Hz), 7.22-7.31(1H, m), 7.61 (1H, brs), 7.90-7.92 (1H, m), 8.22 (1H, brs), 8.81 (1H,brs).

Example 383

By the reaction and treatment in the same manner as in Example 82 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(20.0 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (12.0 g),5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (18.8 g) was obtained. MS (ESI) m/z: 469 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.38-1.49 (1H, m), 1.75-1.82 (2H, m), 1.90-2.00 (1H,m), 2.52-2.55 (2H, m), 3.57 (1H, t, J=6.8 Hz), 3.84 (3H, s), 4.71 (2H,s), 5.08 (2H, s), 6.59-6.62 (1H, m), 6.83-6.90 (2H, m), 7.02-7.07 (1H,m), 7.31-7.46 (7H, m), 7.60-7.64 (1H, m), 8.04 (1H, d, J=2.4 Hz).

Example 384

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.94 g) and benzyl bromide (0.285 mL) as startingmaterials,5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.087 g) was obtained.

MS (ESI) m/z: 469 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.36-1.43 (1H, m), 1.75-1.79 (2H, m), 1.86-2.00 (1H,m), 2.43-2.57 (2H, m), 3.49-3.55 (1H, m), 3.85 (3H, s), 4.68 (2H, s),5.28 (2H, s), 6.40 (1H, d, J=7.8 Hz), 6.60 (1H, d, J=7.8 Hz), 6.82-6.88(2H, m), 7.09 (2H, d, J=6.5 Hz), 7.25-7.36 (4H, m), 7.57-7.62 (2H, m),8.01 (1H, d, J=2.4 Hz), 9.20 (1H, brs).

Example 385

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.94 g) and 2-(chloromethyl)pyridine hydrochloride (0.33g) as starting materials,5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.28 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.085 g) was obtained.

MS (ESI) m/z: 470 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.35-1.43 (1H, m), 1.74-1.80 (2H, m), 1.87-1.95 (1H,m), 2.43-2.56 (2H, m), 3.50-3.55 (1H, m), 3.85 (3H, s), 4.65-5.00 (3H,m), 5.51 (2H, m), 6.43 (1H, d, J=7.8 Hz), 6.61 (1H, d, J=7.8 Hz),6.83-6.90 (2H, m), 7.03 (1H, d, J=7.8 Hz), 7.34 (1H, s), 7.55 (1H, t,J=6.3 Hz), 7.64 (1H, dd, J=2.7, 8.7 Hz), 7.73 (1H, s), 8.00-8.07 (2H,m), 8.66-8.67 (1H, m).

Example 386

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.936 g) and 4-(trifluoromethyl)benzyl chloride (0.592mL) as starting materials,5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.25 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 133,5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g) was obtained. melting point: 199-200° C.

Example 387

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.70 g) and 2-(2-chloroethyl)pyridine (0.42 g) asstarting materials,5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.45 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.31 g) was obtained.

MS (ESI) m/z: 484 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.37-1.41 (1H, m), 1.71-1.77 (2H, m), 1.87-1.92 (1H,m), 2.44-2.52 (2H, m), 3.47-3.57 (3H, m), 3.86 (3H, s), 4.54-4.68 (4H,m), 6.40 (1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.7 Hz), 6.86-6.91 (2H, m),7.12 (1H, s), 7.53-7.58 (2H, m), 7.72 (1H, d, J=8.0 Hz), 7.86-7.90 (1H,m), 7.94 (1H, d, J=2.5 Hz), 8.38-8.41 (1H, m), 8.81 (1H, d, J=4.9 Hz).

Example 388

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.83 g) and 2-(2-chloroethyl)pyridine (0.42 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.56 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.41 g) was obtained.

MS (ESI) m/z: 496 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.32 (6H, d, J=6.9 Hz), 1.37-1.46 (1H, m), 1.79-1.92(3H, m), 2.44-2.56 (2H, m), 3.34 (1H, brs), 3.51-3.60 (1H, m), 3.58 (2H,t, J=6.6 Hz), 4.61 (2H, t, J=6.6 Hz), 4.73-4.78 (2H, m), 6.46 (1H, d,J=7.8 Hz), 6.66 (1H, d, J=7.8 Hz), 6.90 (1H, t, J=7.8 Hz), 7.20 (1H,brs), 7.61 (1H, brs), 7.76 (2H, d, J=7.7 Hz), 7.86-7.92 (1H, m), 8.04(1H, brs), 8.46 (1H, t, J=7.7 Hz), 8.63 (1H, brs), 8.82 (1H, d, J=5.0Hz).

Example 389

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.96 g) and dodecyl bromide (0.719 mL) as startingmaterials,5-benzyloxy-N-[(1-dodecylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.29 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,N-[(1-dodecylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.54 g) was obtained. MS (ESI) m/z: 559 [MH]+

¹H-NMR (DMSO-d₆) δ: 0.82-0.87 (3H, m), 1.12-1.45 (19H, m), 1.32 (6H, d,J=6.9 Hz), 1.64-1.73 (2H, m), 1.82-1.92 (3H, m), 2.40-2.56 (2H, m),3.30-3.40 (1H, m), 3.55 (1H, brs), 4.02 (2H, t, J=6.7 Hz), 4.74-4.82(2H, m), 6.48 (1H, d, J=7.8 Hz), 6.66 (1H, d, J=7.8 Hz), 6.89 (1H, t,J=7.8 Hz), 7.28 (1H, brs), 7.56 (1H, brs), 7.78 (1H, brs), 8.07 (1H,brs), 8.72 (1H, brs).

Example 390

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.96 g) and nonyl bromide (0.57 mL) as startingmaterials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.20 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.81 g) was obtained.

MS (ESI) m/z: 517 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.85 (3H, t, J=6.6 Hz), 1.12-1.45 (13H, m), 1.31(6H, d, J=6.9 Hz), 1.68 (2H, t, J=6.9 Hz), 1.81-1.91 (3H, m), 2.40-2.55(2H, m), 3.33 (1H, brs), 3.54 (1H, brs), 4.02 (2H, t, J=6.9 Hz),4.69-4.81 (2H, m), 6.47 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.8 Hz), 6.88(1H, t, J=7.8 Hz), 7.27 (1H, brs), 7.55 (1H, brs), 7.76 (1H, brs), 8.05(1H, brs), 8.69 (1H, brs).

Example 391

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (3.26 g) and ethyl 7-bromoheptanoate (2.0 mL) as startingmaterials, ethyl7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate(4.25 g) was obtained.

MS (ESI) m/z: 637 [MH]⁺

Example 392

Ethyl7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate(2.0 g) was dissolved in ethanol (100 mL), and 1 mol/L-aqueous sodiumhydroxide solution (6.60 mL) was added. The mixture was stirred at roomtemperature for 1 hr. To the reaction mixture was added 1mol/L-hydrochloric acid (6.60 mL), and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated, andthe residue was purified by silica gel column chromatography to give7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoicacid (1.80 g). By the reaction and treatment of this compound in thesame manner as in Example 139,7-(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoicacid hydrochloride (0.84 g) was obtained.

MS (ESI) m/z: 519 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.13-1.51 (7H, m), 1.32 (6H, d, J=6.8 Hz), 1.64-1.73(2H, m), 1.80-1.99 (3H, m), 2.18 (2H, t, J=7.2 Hz), 2.40-2.57 (2H, m),3.36 (1H, brs), 3.55 (1H, brs), 4.02 (2H, t, J=6.9 Hz), 4.68-4.81 (2H,m), 6.48 (1H, d, J=7.8 Hz), 6.65 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.8Hz), 7.28 (1H, brs), 7.56 (1H, brs), 7.80 (1H, brs), 8.08 (1H, brs),8.74 (1H, brs).

Example 393

By the reaction and treatment in the same manner as in Example 256 usingethyl7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate(2.2 g) as a starting material,5-benzyloxy-N-{[1-(7-hydroxyheptyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.30 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 139,5-hydroxy-N-{[1-(7-hydroxyheptyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.48 g) was obtained.

MS (ESI) m/z: 505 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.04-1.40 (15H, m), 1.64-1.73 (2H, m), 1.85-1.91(3H, m), 2.50-2.52 (2H, m), 3.36 (2H, t, J=6.4 Hz), 3.36-3.40 (1H, m),3.56 (1H, brs), 4.02 (2H, t, J=6.4 Hz), 4.79 (2H, brs), 6.48 (1H, d,J=7.8 Hz), 6.66 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.8 Hz), 7.29 (1H,brs), 7.57 (1H, brs), 7.85 (1H, brs), 8.13 (1H, brs), 8.77 (1H, brs).

Example 394

To a solution of ethylene glycol monobutyl ether (1 mL) andtriethylamine (1.6 mL) in dichloromethane (20 mL) was addedmethanesulfonyl chloride (0.88 mL) under ice-cooling, and the mixturewas stirred at room temperature for one day. The reaction mixture waspartitioned between water and chloroform, washed with saturated brineand dried over magnesium sulfate. The solvent was evaporated, and theobtained residue and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (1.0 g) were reacted and treated in the same manner as inExample 83 to give5-benzyloxy-N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g).

MS (ESI) m/z: 581 [MH]⁺

Example 395

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) as a starting material,N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.25 g) was obtained.

MS (ESI) m/z: 491 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 0.82 (3H, t, J=7.3 Hz), 1.15-1.24 (2H, m), 1.29 (6H,d, J=6.6 Hz), 1.36-1.43 (3H, m), 1.81-1.91 (3H, m), 2.41-2.51 (2H, m),3.21-3.32 (1H, m), 3.32 (2H, t, J=6.6 Hz), 3.53 (1H, brs), 3.65 (2H, t,J=5.4 Hz), 4.18 (2H, t, J=5.4 Hz), 4.70-4.77 (2H, m), 6.47 (1H, d, J=7.8Hz), 6.63 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=7.8 Hz), 7.27 (1H, brs),7.55 (1H, brs), 7.68 (1H, brs), 7.96 (1H, brs), 8.63 (1H, brs).

Example 396

By the reaction and treatment in the same manner as in Example 394 usingdiethylene glycol monomethyl ether (1 mL) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.0 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) was obtained.

MS (ESI) m/z: 583 [MH]+

Example 397

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.20 g) was obtained.

MS (ESI) m/z: 493 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.40 (1H, m), 1.81-1.91 (3H,m), 2.51 (2H, m), 3.19 (3H, s), 3.28-3.32 (1H, m), 3.36-3.39 (2H, m),3.44-3.47 (2H, m), 3.48-3.52 (1H, m), 3.70 (2H, t, J=5.4 Hz), 4.19 (2H,t, J=5.4 Hz), 4.71-4.78 (2H, m), 6.49 (1H, d, J=7.8 Hz), 6.64 (1H, d,J=7.8 Hz), 6.89 (1H, t, J=7.8 Hz), 7.28 (1H, brs), 7.58 (1H, brs), 7.76(1H, brs), 8.04 (1H, brs), 8.70 (1H, brs).

Example 398

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and(4-isopropylphenyl)[(6-morpholinopyridin-3-yl)methyl]amine (0.62 g) asstarting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.90 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.31-1.51 (1H, m), 1.73-2.09(3H, m), 2.49-2.70 (2H, m), 2.90 (1H, sept, J=6.9 Hz), 3.49 (4H, t,J=5.0 Hz), 3.68-3.79 (1H, m), 3.83 (4H, t, J=4.8 Hz), 4.73 (1H, d,J=14.1 Hz), 4.86 (1H, d, J=14.1 Hz), 5.03 (2H, s), 6.55-6.65 (2H, m),6.71 (1H, d, J=8.1 Hz), 6.97-7.10 (3H, m), 7.17-7.45 (7H, m), 7.69 (1H,dd, J=2.1, 8.7 Hz), 7.93 (1H, d, J=2.1 Hz).

Example 399

By the reaction and treatment in the same manner as in Example 105 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.88 g) as a starting material,5-hydroxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.51 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.32-1.51 (1H, m), 1.73-2.08(3H, m), 2.49-2.69 (2H, m), 2.88 (1H, sept, J=6.9 Hz), 3.36-3.58 (4H,m), 3.69-3.90 (5H, m), 4.78 (1H, d, J=14.2 Hz), 4.85 (1H, d, J=14.2 Hz),6.34 (1H, d, J=7.9 Hz), 6.46 (1H, d, J=7.7 Hz), 6.62 (1H, d, J=8.8 Hz),6.78 (1H, t, J=7.8 Hz), 7.02 (2H, d, J=7.9 Hz), 7.20 (2H, d, J=8.3 Hz),7.59 (1H, dd, J=2.1, 8.7 Hz), 7.93 (1H, d, J=2.0 Hz), 7.90-8.38 (1H,brs).

Example 400

By the reaction and treatment in the same manner as in Example 12 using5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and(4-isopropylphenyl)([6-(2-methoxyethoxy)pyridin-3-yl]methyl)amine (0.60g) as starting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-([6-(2-methoxyethoxy)pyridin-3-yl]methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.40-1.59 (1H, m), 1.77-2.10(3H, m), 4.39-4.50 (2H, m), 4.78 (1H, d, J=14.1 Hz), 4.89 (1H, d, J=14.1Hz), 5.03 (2H, s), 6.61 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=8.1 Hz), 6.77(1H, d, J=8.7 Hz), 6.98 (2H, d, J=8.4 Hz), 7.06 (1H, t, J=8.1 Hz),7.17-7.44 (7H, m), 7.61 (1H, dd, J=2.4, 8.4 Hz), 7.86 (1H, d, J=2.4 Hz).

Example 401

By the reaction and treatment in the same manner as in Example 17 using5-benzyloxy-N-(4-isopropylphenyl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.88 g) as a starting material,5-hydroxy-N-(4-isopropylphenyl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.35 g) was obtained. melting point: 153° C.

Example 402

To a solution ofN-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.55 g) in chloroform (10 mL) was added m-chloroperbenzoic acid (0.29g), and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was partitioned between water and chloroform. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to giveN-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropyl-1-oxidopyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.13 g).

MS (ESI) m/z: 515 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.38-1.57 (1H, m), 1.78-2.05(3H, m), 2.48-2.67 (2H, m), 3.57-3.80 (2H, m), 4.61 (1H, d, J=14.7 Hz),4.82 (1H, d, J=15.0 Hz), 5.23 (2H, s), 6.33 (1H, d, J=7.8 Hz), 6.49 (1H,d, J=7.8 Hz), 6.80 (1H, t, J=8.0 Hz), 6.95-7.10 (3H, m), 7.13-7.29 (4H,m), 7.42 (2H, d, J=2.1 Hz), 8.15-8.30 (1H, brs).

Example 403

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.62 g) and 2-(chloromethyl)-4-methylpyridine hydrochloride (0.46 g) asstarting materials,5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.35-1.53 (1H, m), 1.75-2.08(3H, m), 2.30 (3H, s), 2.60-2.80 (2H, m), 2.91 (1H, sept, J=6.9 Hz),3.65-3.77 (1H, m), 4.65 (1H, d, J=14.4 Hz), 4.85 (1H, d, J=14.4 Hz),5.02 (2H, s), 5.37 (2H, s), 6.58 (1H, d, J=7.8 Hz), 6.70 (1H, d, J=8.1Hz), 6.76 (1H, s), 6.92-7.09 (4H, m), 7.17-7.51 (9H, m), 8.41 (1H, d,J=4.8 Hz).

Example 404

By the reaction and treatment in the same manner as in Example 133 using5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g) as a starting material,5-hydroxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.50 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.35-2.08 (4H, m), 2.30 (3H,s), 2.49-2.68 (2H, m), 2.91 (1H, sept, J=6.9 Hz), 3.64-3.76 (1H, m),4.68 (1H, d, J=14.4 Hz), 4.83 (1H, d, J=14.4 Hz), 5.03-5.18 (1H, brs),5.38 (2H, s), 6.45 (2H, t, J=7.8 Hz), 6.73-6.86 (2H, m), 6.98-7.12 (3H,m), 7.18-7.32 (2H, m), 7.46 (1H, s), 7.50 (1H, s), 8.42 (1H, d, J=5.1Hz).

Example 405

By the reaction and treatment in the same manner as in Example 402 using5-hydroxy-N-(4-isopropylphenyl)-N-({1-[4-methylpyridin-2-yl]methyl}pyrazol-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.50 g) as a starting material,5-hydroxy-N-(4-isopropylphenyl)-N-({1-[(4-methyl-1-oxidopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.16 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.35-1.52 (1H, m), 1.76-2.07(3H, m), 2.27 (3H, s), 2.52-2.67 (2H, m), 2.92 (1H, sept, J=6.9 Hz),3.66-3.80 (1H, m), 4.69 (1H, d, J=14.5 Hz), 4.88 (1H, d, J=14.5 Hz),5.56 (2H, s), 6.43 (2H, d, J=7.9 Hz), 6.51 (1H, d, J=1.6 Hz), 6.78 (1H,t, J=7.8 Hz), 7.00-7.17 (3H, m), 7.20-7.31 (2H, m), 7.54 (1H, s), 7.58(1H, s), 8.18 (1H, d, J=6.6 Hz).

Example 406

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 5-chloromethyl-2-ethoxypyridine (0.51 g) asstarting materials,5-benzyloxy-N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.38 (3H, t, J=7.1 Hz),1.39-1.57 (1H, m), 1.78-2.08 (3H, m), 2.60-2.80 (2H, m), 3.08 (1H, sept,J=6.9 Hz), 3.57-3.67 (1H, m), 4.35 (2H, q, J=7.1 Hz), 4.59 (1H, d,J=14.4 Hz), 4.83 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.17 (2H, s), 6.49(1H, d, J=7.8 Hz), 6.65-6.77 (2H, m), 7.01 (1H, t, J=8.0 Hz), 7.17 (1H,d, J=8.4 Hz), 7.22-7.48 (9H, m), 8.04 (1H, d, J=2.4 Hz), 8.36 (1H, d,J=2.4 Hz).

Example 407

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.66 g) as a starting material,N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.54 g) was obtained.

MS (ESI) m/z: 526 [MH]⁺

Example 408

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.65 g) and 6-chloromethyl-2-morpholinopyridine (0.29 g)as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.39-1.57 (1H, m), 1.77-2.08(3H, m), 2.60-2.81 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.49 (4H, t,J=4.8 Hz), 3.58-3.69 (1H, m), 3.80 (4H, t, J=5.0 Hz), 4.66 (1H, d,J=14.4 Hz), 4.85 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.23 (2H, s), 6.28(1H, d, J=7.2 Hz), 6.46-6.58 (2H, m), 6.71 (1H, d, J=8.1 Hz), 7.00 (1H,t, J=7.8 Hz), 7.18 (1H, d, J=8.4 Hz), 7.25-7.51 (9H, m), 8.39 (1H, d,J=2.4 Hz).

Example 409

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.30 g) was obtained. MS (ESI) m/z: 567 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.30 (6H, d, J=6.9 Hz), 1.34-1.52 (1H, m), 1.68-1.93(3H, m), 2.34-2.58 (2H, m), 3.20-3.70 (10H, m), 5.30 (2H, s), 6.13 (1H,d, J=7.2 Hz), 6.47 (1H, d, J=7.8 Hz), 6.64 (1H, d, J=7.8 Hz), 6.78-6.90(2H, m), 7.27-7.44 (1H, m), 7.61 (1H, t, J=7.8 Hz), 7.67-7.83 (2H, m),7.97-8.17 (1H, m), 8.61-8.80 (1H, m).

Example 410

By the reaction and treatment in the same manner as in Example, 271using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 5-chloromethyl-2-(2-methoxyethoxy)pyridine(0.61 g) as starting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.77 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.40-1.57 (1H, m), 1.75-2.05(3H, m), 2.60-2.80 (2H, m), 3.08 (1H, sept, J=6.9 Hz), 3.39-3.49 (3H,m), 3.55-3.65 (1H, m), 3.68-3.78 (2H, m), 4.42-4.51 (2H, m), 4.59 (1H,d, J=14.7 Hz), 4.83 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.17 (2H, s), 6.49(1H, d, J=7.8 Hz), 6.72 (1H, d, J=8.1 Hz), 6.80 (1H, t, J=9.3 Hz), 7.01(1H, t, J=7.8 Hz), 7.17 (1H, d, J=8.4 Hz), 7.24-7.48 (9H, m), 8.03 (1H,d, J=2.4 Hz), 8.37 (1H, d, J=2.4 Hz).

Example 411

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.76 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.55 g) was obtained.

MS (ESI) m/z: 556 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.31 (6H, d, J=6.9 Hz), 1.34-1.53 (1H, m), 1.68-1.93(3H, m), 2.35-2.60 (2H, m), 3.29-3.67 (7H, m), 4.29-4.39 (2H, m),4.63-4.90 (2H, m), 5.22 (2H, s), 6.45 (1H, d, J=7.6 Hz), 6.64 (1H, d,J=7.8 Hz), 6.77-6.90 (2H, m), 7.22-7.38 (1H, m), 7.55 (1H, dd, J=2.4,8.5 Hz), 7.60-7.89 (2H, m), 8.00-8.16 (2H, m), 8.67-8.82 (1H, m).

Example 412

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and 6-chloromethyl-2-methoxypyridine (0.47 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.44 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.40-1.60 (1H, m), 1.77-2.08(3H, m), 2.61-2.82 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.60-3.70 (1H,m), 3.88 (3H, s), 4.66 (1H, d, J=14.7 Hz), 4.86 (1H, d, J=14.4 Hz), 5.03(2H, s), 5.28 (2H, s), 6.53 (2H, t, J=6.6 Hz), 6.64 (1H, d, J=8.4 Hz),6.71 (1H, d, J=8.1 Hz), 7.00 (1H, t, J=7.8 Hz), 7.18 (1H, d, J=8.4 Hz),7.25-7.56 (9H, m), 8.39 (1H, d, J=2.1 Hz).

Example 413

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.43 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-(({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.34 g) was obtained. MS (ESI) m/z: 512 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.27 (6H, d, J=6.9 Hz), 1.31-1.53 (1H, m), 1.69-1.99(3H, m), 2.34-2.60 (2H, m), 3.13-3.32 (1H, m), 3.43-3.62 (1H, m), 3.80(3H, s), 4.65-4.90 (2H, m), 5.29 (2H, s), 6.39 (1H, d, J=7.2 Hz), 6.46(1H, d, J=7.8 Hz), 6.62 (1H, d, J=7.8 Hz), 6.73 (1H, d, J=8.4 Hz), 6.86(1H, t, J=7.8 Hz), 7.25-7.44 (1H, m), 7.55-8.05 (4H, m), 8.49-8.73 (1H,m).

Example 414

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.78 g) and isopropyl iodide (0.30 mL) as startingmaterials,5-benzyloxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.68 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 1.39-1.58 (7H, m), 1.78-2.07(3H, m), 2.62-2.83 (2H, m), 3.09 (1H, sept, J=6.9 Hz), 3.58-3.68 (1H,m), 4.47 (1H, sept, J=6.6 Hz), 4.58 (1H, d, J=14.7 Hz), 4.90 (1H, d,J=14.4 Hz), 5.03 (2H, s), 6.52 (1H, d, J=7.8 Hz), 6.72 (1H, d, J=8.1Hz), 7.02 (1H, t, J=7.8 Hz), 7.19 (1H, d, J=8.1 Hz), 7.25-7.47 (8H, m),8.38 (1H, d, J=2.4 Hz).

Example 415

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.67 g) as a starting material,5-hydroxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.52 g) was obtained.

MS (ESI) m/z: 433 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.22-1.60 (13H, m), 1.72-1.98 (3H, m), 2.36-2.64(2H, m), 3.21-3.63 (2H, m), 4.30-5.07 (3H, m), 6.46 (1H, d, J=7.6 Hz),6.63 (1H, d, J=7.8 Hz), 6.88 (1H, t, J=7.8 Hz), 7.20-7.37 (1H, m),7.47-7.63 (1H, m), 7.68-7.87 (1H, m), 7.97-8.13 (1H, m), 8.59-8.80 (1H,m).

Example 416

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and[(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.54 g)as starting materials,N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.13 g) was obtained.

MS (ESI) m/z: 458 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.9 Hz), 1.40-1.65 (1H, m), 1.80-2.10(3H, m), 2.50-2.85 (2H, m), 2.93 (6H, s), 3.00-3.15 (1H, m), 3.55-3.65(1H, m), 3.69 (3H, s), 4.60 (1H, d, J=13.8 Hz), 5.07. (1H, d, J=13.8Hz), 6.48 (1H, d, J=2.4 Hz), 6.55-6.75 (3H, m), 6.90-7.30 (5H, m), 8.29(1H, d, J=2.4 Hz).

Example 417

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.96 g) and 2-(chloromethyl)thiophene (0.25 g) as a starting material,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.95 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 133,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.41 g) was obtained. melting point: 125-129° C.

Example 418

By the reaction and treatment in the same manner as in Example 83 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.44 g) and 2-chloro-5-(chloromethyl)thiophene (0.79 g) as startingmaterials,5-benzyloxy-N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.37 g) was obtained. By the reaction and treatment of this compound inthe same manner as in Example 133,N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.37 g) was obtained. melting point: 98-101° C.

Example 419

By the reaction and treatment of diethylene glycol monobutyl ether (1.0mL) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.96 g) in the same manner as in Example 394,5-benzyloxy-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.94 g) was obtained.

MS (ESI) m/z: 625 [MH]⁺

Example 420

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.94 g) as a starting material,N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.48 g) was obtained.

MS (ESI) m/z: 535 [MH]⁺

¹H-NMR (DMSO-d₆) δ: (0.85 (3H, t, J=7.2 Hz), 1.21-1.48 (11H, m),1.80-1.85 (3H, m), 2.51 (2H, brs), 3.26 (2H, t, J=6.5 Hz), 3.42-3.58(6H, m), 3.71 (2H, t, J=5.2 Hz), 4.20 (2H, t, J=5.2 Hz), 4.73-4.82 (2H,m), 6.50 (1H, d, J=7.7 Hz), 6.67 (1H, d, J=7.7 Hz), 6.90 (1H, t, J=7.7Hz), 7.32 (1H, brs), 7.61 (1H, brs), 7.92 (1H, brs), 8.21 (1H, brs),8.81 (1H, brs).

Example 421

By the reaction and treatment of diethylene glycol monoethyl ether (1.5mL) and5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.72 g) in the same manner as in Example 394,5-benzyloxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.89 g) was obtained.

MS (ESI) m/z: 597 [MH]⁺

Example 422

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.00 g) as a starting material,5-hydroxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.15 g) was obtained.

MS (ESI) m/z: 507 [MH]⁺

¹H-NMR (DMSO-d₆) δ: 1.06 (3H, t, J=7.0 Hz), 1.32 (1H, d, J=6.8 Hz),1.43-1.48 (1H, m), 1.81-1.91 (3H, m), 2.50 (2H, brs), 3.34-3.55 (8H, m),3.70 (2H, t, J=5.3 Hz), 4.19 (2H, t, J=5.3 Hz), 4.71-4.79 (2H, m), 6.48(1H, d, J=7.7 Hz), 6.65 (1H, d, J=7.7 Hz), 6.90 (1H, t, J=7.7 Hz), 7.29(1H, brs), 7.59 (1H, brs), 7.79 (1H, brs), 8.08 (1H, brs), 8.72 (1H,brs).

Example 423

By the reaction and treatment in the same manner as in Example 12 using7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.64 g) and(4-isopropylphenyl){[4-(2,2,2-trifluoroethoxy)phenyl]methyl}amine (1.0g) as starting materials,N-(4-isopropylphenyl)-7-methoxy-N-{[4-(2,2,2-trifluoroethoxy)phenyl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.58 g) was obtained. melting point: 125-127° C.

Example 424

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.94 g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.71 g) asstarting materials,5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.90 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.39-1.57 (1H, m), 1.76-2.12 (3H, m), 2.31 (3H, s),2.61-2.82 (2H, m), 3.62-3.82 (1H, m), 3.93 (3H, s), 4.65 (1H, d, J=14.4Hz), 4.84 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.36 (2H, s), 6.55 (1H, d,J=7.8 Hz), 6.68-6.83 (3H, m), 6.95-7.07 (8H, m), 7.98 (1H, d, J=2.4 Hz),8.41 (1H, d, J=5.1 Hz).

Example 425

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.90 g) as a starting material,5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.67 g) was obtained. MS (ESI) m/z: 484 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.22-1.51 (1H, m), 1.80-2.00 (3H, m), 2.35-2.62 (5H,m), 3.47-3.57 (1H, m), 3.84 (3H, s), 4.67 (1H, d, J=14.6 Hz), 4.76 (1H,d, J=14.7 Hz), 5.71 (2H, s), 6.45 (1H, d, J=7.7 Hz), 6.63 (1H, d, J=7.8Hz), 6.80-6.92 (2H, m), 7.24 (1H, s), 7.38 (1H, s), 7.70 (1H, dd, J=2.6,8.7 Hz), 7.77 (1H, d, J=5.8 Hz), 7.85 (1H, s), 8.07 (1H, d, J=2.4 Hz),8.74 (1H, d, J=5.9 Hz).

Example 426

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.94 g) and 2-chloromethyl-5-methylpyridine hydrochloride (0.71 g) asstarting materials,5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.94 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.39-1.57 (1H, m), 1.76-2.12 (3H, m), 2.31 (3H, s),2.61-2.82 (2H, m), 3.62-3.82 (1H, m), 3.93 (3H, s), 4.65 (1H, d, J=14.4Hz), 4.84 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.35 (2H, s), 6.54 (1H, d,J=7.7 Hz), 6.64-6.77 (2H, m), 6.88 (1H, d, J=8.0 Hz), 7.01 (1H, t, J=7.9Hz), 7.23-7.52 (9H, m), 7.97 (1H, d, J=2.5 Hz), 8.38 (1H, d, J=1.7 Hz).

Example 427

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.94 g) as a starting material,5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.73 g) was obtained. MS (ESI) m/z: 484 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.30-1.52 (1H, m), 1.68-1.98 (3H, m), 2.33-2.57 (5H,m), 3.45-3.57 (1H, m), 3.85 (3H, s), 4.66 (1H, d, J=15.0 Hz), 4.74 (1H,d, J=14.7 Hz), 5.61 (2H, s), 6.43 (1H, d, J=7.5 Hz), 6.62 (1H, d, J=7.8Hz), 6.79-6.93 (2H, m), 7.22 (1H, d, J=8.1 Hz), 7.34 (1H, s), 7.65 (1H,dd, J=2.7, 8.7 Hz), 7.79 (1H, s), 8.02-8.18 (2H, m), 8.68 (1H, s).

Example 428

By the reaction and treatment in the same manner as in Example 271 using5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.94 g) and 6-chloromethyl-2-(dimethylamino)pyridine (0.68 g) asstarting materials,5-benzyloxy-N-({1-[(6-(dimethylamino)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) was obtained. ¹H-NMR (CDCl₃) δ: 1.38-1.67 (1H, m), 1.73-2.07(3H, m), 2.61-2.82 (2H, m), 3.04 (6H, s), 3.59-3.72 (1H, m), 3.93 (3H,s), 4.64 (1H, d, J=14.4 Hz), 4.83 (1H, d, J=14.4 Hz), 5.03 (2H, s), 5.21(2H, s), 6.18 (1H, d, J=7.2 Hz), 6.40 (1H, d, J=8.4 Hz), 6.54 (1H, d,J=7.5 Hz), 6.62-6.76 (2H, m), 7.01 (1H, t, J=8.0 Hz), 7.21-7.52 (9H, m),7.99 (1H, d, J=2.4 Hz).

Example 429

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-({1-[(6-(dimethylamino)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.31 g) as a starting material,N-({1-[(6-(dimethylamino)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidedihydrochloride (0.20 g) was obtained. MS (ESI) m/z: 513 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.30-1.50 (1H, m), 1.68-2.00 (3H, m), 2.34-2.58 (2H,m), 3.17 (6H, s), 3.30-3.78 (1H, m), 3.84 (3H, s), 4.67 (1H, d, J=14.8Hz), 4.74 (1H, d, J=14.7 Hz), 5.45 (2H, s), 6.06 (1H, d, J=7.1 Hz), 6.43(1H, d, J=7.6 Hz), 6.61 (1H, d, J=7.8 Hz), 6.80-6.97 (3H, m), 7.35 (1H,s), 7.60-7.81 (3H, m), 8.06 (1H, d, J=2.4 Hz).

Example 430

By the reaction and treatment in the same manner as in Example 132 using5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.43 g) and 5-chloromethyl-2-ethyl-4-methylthiazole (0.68 g) asstarting materials,5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.92 g) was obtained.

¹H-NMR (CDCl₃) δ: 1.33 (3H, t, J=7.5 Hz), 1.40-1.57 (1H, m), 1.75-2.12(6H, m), 2.36 (3H, s), 2.66-2.80 (2H, m), 2.92 (2H, q, J=7.6 Hz),3.68-3.81 (1H, m), 5.03 (2H, s), 5.10 (1H, d, J=15.0 Hz), 5.17 (1H, d,J=15.0 Hz), 6.72 (1H, d, J=3.3 Hz), 6.75 (1H, d, J=2.7 Hz), 6.88-7.00(1H, m), 7.07 (1H, t, J=8.0 Hz), 7.25-7.52 (6H, m), 8.40 (1H, d, J=2.1Hz).

Example 431

By the reaction and treatment in the same manner as in Example 101 using5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.92 g) as a starting material,N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-5-hydroxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamidehydrochloride (0.57 g) was obtained. MS (ESI) m/z: 422 [MH]+

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.5 Hz), 1.35-1.50 (1H, m), 1.73-1.99(3H, m), 2.16 (3H, s), 2.34 (3H, s), 2.42-2.58 (2H, m), 3.10 (2H, q,J=7.5 Hz), 3.62-3.77 (1H, m), 5.03 (2H, s), 6.44 (1H, d, J=7.6 Hz), 6.43(1H, d, J=7.7 Hz), 6.85 (1H, t, J=7.8 Hz), 7.40 (1H, d, J=8.0 Hz), 7.80(1H, dd, J=2.1, 8.1 Hz), 8.42 (1H, d, J=2.3 Hz).

Example 432

By the reaction and treatment in the same manner as in Example 142 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.53 g) and 2-(2-butoxyethoxy)-5-(hydroxymethyl)pyridine (0.30 g) asstarting materials,5-benzyloxy-N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.40 g) was obtained.

MS (ESI) m/z: 608 [MH]⁺

Example 433

By the reaction and treatment in the same manner as in Example 139 using5-benzyloxy-N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.40 g) as a starting material,N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.10 g) was obtained. MS (ESI) m/z: 518 [MH]+

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.2 Hz), 1.30 (6H, d, J=6.9 Hz),1.20-2.15 (8H, m), 2.50-2.70 (2H, m), 3.00-3.20 (1H, m), 3.54 (2H, t,J=6.6 Hz), 3.60-3.70 (1H, m), 3.75-3.85 (2H, m), 4.40-4.50 (2H, m), 4.83(1H, d, J=14.1 Hz), 4.90 (1H, d, J=14.1 Hz), 6.35-6.50 (2H, m),6.75-6.90 (2H, m), 7.19 (1H, d, J=8.4 Hz), 7.25-7.35 (1H, m), 7.61 (1H,dd, J=2.4, 8.4 Hz), 7.85 (1H, d, J=2.4 Hz), 8.34 (1H, d, J=2.4 Hz).

Example 434

By the reaction and treatment in the same manner as in Example 132 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide(2.05 g) and 4-chloromethyl-1-(2,2,2-trifluoroethyl)pyrazole (1.02 g) asstarting materials,5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(1.70 g) was obtained.

MS (ESI) m/z: 563 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=7.2 Hz), 1.40-1.65 (1H, m), 1.75-2.10(3H, m), 2.60-2.85 (2H, m), 3.00-3.20 (1H, m), 3.60-3.70 (1H, m),4.55-4.75 (3H, m), 4.87 (1H, d, J=14.4 Hz), 5.03 (2H, s), 6.51 (1H, d,J=7.8 Hz), 6.73 (1H, d, J=7.8 Hz), 7.04 (1H, t, J=7.8 Hz), 7.15-7.60(9H, m), 8.39 (1H, d, J=2.4 Hz).

Example 435

By the reaction and treatment in the same manner as in Example 17 using5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.81 g) as a starting material,5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide(0.23 g) was obtained. melting point: 127.7° C.

MS (ESI) m/z: 473 [MH]⁺

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.3 Hz), 1.35-1.55 (1H, m), 1.75-2.10(3H, m), 2.50-2.70 (2H, m), 3.00-3.20 (1H, m), 3.60-3.70 (1H, m),4.55-4.75 (3H, m), 4.85 (1H, d, J=14.5 Hz), 6.35-6.45 (2H, m), 6.82 (1H,t, J=7.8 Hz), 6.91 (1H, brs), 7.20-7.55 (4H, m), 8.40 (1H, d, J=2.3 Hz).

Formulation Example 1

The compound of the present invention (50 mg) is thoroughly kneaded withlactose (98 mg), cornstarch (45 mg) and hydroxypropyl cellulose (3 mg)in a kneader. The kneaded product is passed through a 200 mesh sieve,dried at 50° C. and passed through a 24 mesh sieve. Talc (3 mg) andmagnesium stearate (1 mg) were mixed and, using a 9 mm diameter pounder,tablets weighing 200 mg are obtained. These tablets may be sugar-coatedor film-coated as necessary.

Pharmaceutical Preparation Example 1

Tablets containing the following ingredients were produced by aconventional method.

ingredients per tablet compound of Example 4 10 mg lactose 125 mg cornstarch 75 mg talc 4 mg magnesium stearate 1 mg total weight 215 mg

Pharmaceutical Preparation Example 2

Capsules containing the following ingredients were produced by aconventional method.

ingredients per capsule compound of Example 4 10 mg lactose 165 mg cornstarch 20 mg talc 5 mg weight of a capsule 200 mg

Pharmaceutical Preparation Example 3

Ointment containing the following ingredients was produced by aconventional method.

ingredients dose compound of Example 4 0.2 g white petrolatum 97.8 gliquid paraffin 2 g total weight 100 g

Pharmaceutical Preparation Example 4

Injection containing the following ingredients was produced by aconventional method.

ingredients dose compound of Example 4  0.2 g sodium chloride  0.9 gdistilled water for injection suitable amount total weight 100 g

Pharmaceutical Preparation Example 5

Eye drop containing the following ingredients was produced by aconventional method.

ingredients compound of Example 4  0.1 g sodium chloride  0.3 g sterilepurified water suitable amount total weight 100 g

The superior pharmacological effect of the compound of the formula (1)is verified by a series of the following tests.

Test Example 1 C5a Receptor Binding Assay

The C5a receptor binding inhibitory action of C5a and the test compoundwas evaluated by a receptor binding assay comprising reacting human cellline U-937 (human histiocytic lymphoma line), which expresses the C5areceptor, with [¹²⁵I]-human C5a (Amersham Pharmacia Biotech) in aMultiScreen (MILLIPORE). First, U-937 cell was stimulated with 1 mMdibutyryl cyclic AMP (dcAMP, SIGMA) for 2 days to express the C5areceptor (dcAMP-U937 cell), and suspended in a binding buffer [50 mMHEPES, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% bovine albumin (BSA, SIGMA), 0.02%NaN₃ (pH 7.2)] and stored at −80° C. The binding assay was started bythe addition of 1×10⁵ cells/50 μL of dcAMP-U937 cell suspensiondissolved immediately before use, 25 μL of a test compound solution(obtained by dissolving the test compound in N,N-Dimethylformamide to afinal concentration of 10 mmol/L and diluting with binding buffer), and25 μL of [¹²⁵I]-C5a solution (final concentration 200 pM), to each wellof the MultiScreen. For calculation of non-specific binding, wellscontaining a non-labeled C5a (final concentration 20 nM) or bindingbuffer instead of the test compound were prepared. After incubation at4° C. for 2 hr, suction filtration and addition of 300 μL of the bindingbuffer were repeated 4 times to remove non-binding portion. After dryingthe MultiScreen, the radioactivity on the filter was measured using agamma counter.

The rate (% inhibition) of inhibition of C5a binding by the testcompound was calculated by the following formula using the count valueobtained without addition of the test compound as Total, the count valueobtained with addition of non-labeled C5a as Non, and the count valueobtained with addition of the test compound as Test.% Inhibition=100−[(Test-Non)/(Total-Non)]×100

Further, the concentration (IC₅₀ value) of the test compound, at whichbinding of [¹²⁵I]-human C5a is inhibited by 50%, was calculated bytwo-interpolation method. In this evaluation system, IC₅₀ value of thecompound of Example 4 was 104 nmol/L.

Test Example 2 Action on Increase of Intracellular Ca²⁺ Concentration ofC5a Stimulated Neutrophil

A neutrophil fraction was separately taken from human peripheral venousblood using Lympholyte-poly (Cedarlane), and suspended in Hank'sBalanced Salt Solution (HBSS, GIBCO BRL) supplemented with 1% fetalbovine serum (FBS). Then, Fura 2-AM (final concentration 5 μM, DOJINDO)was added to the neutrophil fraction (5×10⁶ cells/mL), and the mixturewas incubated at 37° C. for 40 min. The cells were washed bycentrifugation and suspended to the concentration of 1×10⁶ cells/mL. Theintracellular Ca²⁺ concentration was measured using aspectrophotofluorometer (CAF-110, JASCO Corporation), and calculatedfrom the ratio (Ex340 value/Ex380 value) of fluorescent intensities at500 nm upon excitation at 340 nm and 380 nm, the former being Ex340value, the latter being Ex380 value. To be specific, a neutrophilsuspension (450 μL, 1×10⁶ cells/mL) was dispensed to a cuvette having astirrer bar at 5 min before the measurement and the suspension washeated to 37° C. Then the cuvette was set on CAF-110 set for 37° C., andthe measurement was started. Immediately thereafter, 50 μL of a testcompound solution was added. About 45 sec later, 5 μL of recombinanthuman C5a (final concentration 100 pmol/L) was added and the measurementwas continued for about 1 min. Then, Triton X-100 (final concentration0.2%) was added and the cells were dissolved, and sb2 value, which wasthe Ex340 value then, and Rmax value, which was the Ex340 value/Ex380value then, was measured. Then, EGTA (final concentration 3 mmol/L) wasadded and sf2 value, which was the Ex340 value then, and Rmin value,which was the Ex340/Ex380 value then, was measured. From thesemeasurement results, the intracellular Ca²⁺ concentration was calculatedfrom the following formula.

${{Intracellular}\mspace{14mu}{Ca}^{2 +}\mspace{14mu}{concentration}\mspace{14mu}\left( {{nmol}/L} \right)} = {\frac{\left( {{Ex340}\mspace{14mu}{{value}/{Ex380}}\mspace{14mu}{value}} \right) - {{Rmin}\mspace{14mu}{value}}}{{{Rmax}\mspace{14mu}{value}} - \left( {{Ex340}\mspace{14mu}{{value}/{Ex380}}\mspace{14mu}{value}} \right)} \times 224 \times \left( {{sf}\;{2/{sb}}\; 2} \right)}$

In the formula, the Ex340 value/Ex380 value is the value at eachcontinuous point over the entire period of measurement.

The rate (% inhibition) of the inhibition of increase in intracellularCa²⁺ concentration of C5a stimulated neutrophil by the test compound wascalculated by the following formula, wherein the peak value of increasein intracellular Ca²⁺ concentration derived by C5a without addition ofthe test compound is Max, the peak value of intracellular Ca²⁺concentration without addition of the test compound and withoutstimulation with C5a is Min, and the peak value of increase inintracellular Ca²⁺ concentration derived by C5a with the addition of thetest compound is Test.% Inhibition=100−[(Test-Min)/(Max-Min)]×100

Further, the concentration (IC₅₀ value) of the test compound, at whichincrease in intracellular Ca²⁺ concentration of C5a-stimulatedneutrophil is inhibited by 50%, was calculated by two-interpolationmethod.

The IC₅₀ value of the compound of Example 4 was 5 nmol/L. Moreover,addition of the compound of Example 4 (3 μmol/L) did not induce anincrease in intracellular Ca²⁺ and the agonistic action was not found.

Test Example 3 Action of C5a-Stimulated Neutrophil on Production ofReactive Oxygen Species

A neutrophil fraction was separately taken from human peripheral venousblood using Lympholyte-poly (Cedarlane), and suspended in Hank'sBalanced Salt Solution (HBSS, GIBCO BRL) containing 1% fetal bovineserum (FBS) and 1 mmol/L of luminol (Wako Pure Chemical Industries,Ltd.). Reactive oxygen species was measured using a luminometer(MicroLumat, Berthold) for 96 well plate. That is, 1×10⁵ cells/150 μL ofneutrophil suspension and 25 μL of a test compound solution (obtained bydissolving the test compound in N,N-Dimethyl formamide to a finalconcentration of 10 mmol/L and diluting with HBSS supplemented with 1%FBS) were added to a well, which was set in a MicroLumat set for 37° C.and stood for about 5 min. Then, 25 μL of C5a (final concentration 3nmol/L) was added and luminescence produced by the reaction of theluminol and the reactive oxygen species was measured with the lapse oftime for 15 min. The rate (% inhibition) of inhibition of the productionof reactive oxygen species in C5a stimulated neutrophil by the testcompound was calculated by the following formula, wherein the peak valueof the production of reactive oxygen species derived by C5a withoutaddition of the test compound is Max, the peak value of the productionof reactive oxygen species without addition of the test compound andwithout C5a stimulation is Min, and the peak value of the production ofreactive oxygen species derived by C5a with the addition of the testcompound is Test.% Inhibition=100−[(Test-Min)/(Max-Min)]×100

In addition, the concentration (IC₅₀ value) of the test compound, atwhich the production of reactive oxygen species in C5a stimulatedneutrophil is inhibited by 50%, was calculated by two-interpolationmethod.

The IC₅₀ value of the compound of Example 4 was 10 nmol/L.

Test Example 4 Action on Migrating Ability of C5a-Stimulated Neutrophil

A neutrophil fraction was separately taken from human peripheral venousblood using Lympholyte-poly (Cedarlane) and suspended in RPMI 1640medium (GIBCO BRL) supplemented with 0.1% bovine serum albumin (BSA).To. this neutrophil fraction (5×10⁶ cells/mL) was added Calcein-AM(final concentration 5 μM, FUNAKOSHI), and the mixture was incubated at37° C. for 30 min. The cells were washed by centrifugation and suspendedto a concentration of 1×10⁶ cells/mL. The migration was evaluated byadding neutrophils to chemotaxicell (pore size: 3 μm, KURABO) andmeasuring the neutrophils that migrated outside the chemotaxicell.First, 100 pmol/L of C5a solution was added to 24 well plate (500μL/well) and chemotaxicell was set in the well. Then, neutrophilsuspension and test compound solution (200 μL each) were added to theinside of the chemotaxicell and incubated at 37° C., 5% CO₂ for 90 min.After the completion of the reaction, chemotaxicell was removed aftershaking well and 100 μL of cell lysate solution (10% SDS, 0.01 mol/LHCl) was added. The fluorescent intensity of each well was measured byCyto Fluor II (Ex: 485, Em: 530). The rate (% inhibition) of theinhibition of migration of C5a-stimulated neutrophil by the testcompound was calculated by the following formula, wherein thefluorescence intensity of neutrophil that migrated by C5a stimulationwithout addition of the test compound is Max, the fluorescent intensityof neutrophil that migrated without addition of test compound andwithout C5a stimulation is Min, and the fluorescent intensity ofneutrophil that migrated by C5a stimulation with the addition of thetest compound is Test.% Inhibition=100−[(Test-Min)/(Max-Min)]×100

Further, the concentration (IC₅₀ value) of the test compound, at whichmigration of C5a-stimulated neutrophil is inhibited by 50%, wascalculated by two-interpolation method.

The IC₅₀ value of the compound of Example 4 was 100 nmol/L.

Test Example 5 Action on C5a Induced Neutrophil Decrease in Monkey

The test compound is intravenously, subcutaneously or orallyadministered to cynomolgus monkey. Then human C5a (SIGMA) isintravenously administered. The peripheral neutrophil count is takenwith the lapse of time, and suppressive action by the test compound onthe decrease in peripheral neutrophil count is evaluated.

Test Example 6 Action on Collagen-Induced Arthritis in Monkey

Type II collagen derived from bovine (purchased from Collagen ResearchCenter) is intradermally inoculated twice to the back of cynomolgusmonkey, together with complete Freund's adjuvant H37Rv (purchased fromWako Pure Chemical Industries, Ltd.) on the first day of testing and day21. The test compound is orally administered from day 22 to day 33 afterinoculation. The swelling of four limb joints is observed according tothe scores of 0 (no change)-3 (edema of 5 toes). The joint swellingscore of each monkey is shown by the total scores of four limbs.

Test Example 7 Toxicity Test

In a single administration toxicity test, the test compound isadministered to male and female SD rats (3 per group) and cynomolgusmonkey (1 per group) and the toxicity by single administration isevaluated using the presence or absence of death incident, generalcondition and body weight as indices. In a repeat administrationtoxicity test, the test compound is repeatedly administered to male andfemale SD rats (6 per group) and male and female cynomolgus monkeys (2per group) for 2 weeks and the toxicity of the test compound by repeatadministration is evaluated using general condition, body weight, dietintake, hematological test, biochemical test for blood, weight of organsand autopsy (including pathological test of tissues) as indices.

Test Example 8 Evaluation of Bioavailability in Rat

The test compound is intravenously and orally administered to male SDrats (5 per group), and the blood is drawn with the lapse of time. Usinghigh performance liquid chromatography, the drug concentration in plasmais measured. The bioavailability (BA) is calculated by the followingformula.

$\begin{matrix}{\frac{{{AUC}\mspace{14mu}{by}\mspace{14mu}{oral}\mspace{14mu}{administration}}\;}{{{AUC}\mspace{14mu}{by}\mspace{14mu}{intravenous}}\mspace{11mu}{\mspace{31mu}\;}{administration}} \times \frac{{{dose}\mspace{14mu}{of}\mspace{14mu}{intravenous}}\mspace{14mu}\mspace{34mu}{administration}}{\mspace{14mu}{{{dose}\mspace{14mu}{of}\mspace{14mu}{oral}}\mspace{11mu}\;{administration}}} \times 100\mspace{11mu}(\%)} \\{{{AUC}\text{:}\mspace{14mu}{Plasma}\mspace{14mu}{concentration}} - {{area}\mspace{14mu}{under}\mspace{14mu}{time}\mspace{14mu}{curve}}}\end{matrix}$

INDUSTRIAL APPLICABILITY

The compound of the formula (1) of the present invention, an opticallyactive form thereof and pharmaceutical acceptable salt thereof have aC5a receptor antagonistic action and are useful as an agent for theprophylaxis or treatment of diseases or syndromes due to inflammationcaused by C5a [e.g., autoimmune diseases such as rheumatism, systemiclupus erythematosus and the like, sepsis, adult respiratory distresssyndrome, chronic obstructive pulmonary disease, allergic diseases suchas asthma and the like, atherosclerosis, cardiac infarction, braininfarction, psoriasis, Alzheimer's disease and serious organ injury(e.g., pneumonia, nephritis, hepatitis and pancreatitis and the like)due to activation of leukocytes caused by ischemia reperfusion, trauma,burn, surgical invasion and the like]. In addition, it is useful as anagent for the prophylaxis or treatment of infectious diseases caused bybacteria or virus that invades via a C5a receptor.

This application is based on a patent application Nos. 280540/2000 and386813/2000 filed in Japan, the contents of which are herebyincorporated by reference.

1.N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydro-naphthalene-1-carboxamideor a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein saidN-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydro-naphthalene-1-carboxamideor pharmaceutically acceptable salt thereof is a racemic mixture.